HCV inhibitors

ABSTRACT

The present invention is directed to compounds that are antiviral agents. Specifically the compounds of the present invention inhibit replication of HCV and are therefore useful in treating hepatitis C infections. The present invention is also directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional application Ser.No. 60/695,767 filed Jun. 30, 2005, the disclosure of which isincorporated herein by reference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH OR DEVELOPMENT

Not Applicable

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK.

Not Applicable

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to compounds that inhibit HCVreplication and are therefore useful in treating hepatitis C. Thepresent invention is also directed to pharmaceutical compositionscomprising these compounds and processes for preparing them.

2. State of the Art

Hepatitis C virus (HCV) is a (+)-sense single-standed RNA virus that isa major cause of non-A, non-B hepatitis worldwide. A large percentage ofpeople infected with HCV develop chronic liver disease. This chronichepatitis C infection, in turn, makes them at high risk for developingserious liver diseases such as liver cirrhosis, hepatocellular carcinomaand terminal liver disease leading to death. Currently, hepatitits Cinfections are treated with either injectable interferon or withpegylated forms of interferon such as PEG-Intron® and Pegasys®, alone orin combination with Ribavirin. These therapies, however, induce severeside effects such as retinopathy, thyroiditis, acute pancreatitis,depression. Therefore, there is a need for safe, oral drug for thetreatment of hepatitis C infections. The present invention fulfils thisand related needs.

BRIEF SUMMARY OF THE INVENTION

In one aspect, this invention is directed to a compound of Formula (I):

where:

E is —COCONR⁵R⁶, —COCF₂CONR⁵R⁶, —COCF₂C(O)OR⁵, —COCOR⁷, —COCF₂R⁸, —COR⁹,—COCOOR¹⁰, —CONR¹¹R¹², or —B(OR¹³)₂ where R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹²and each R¹³ is independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl and R⁸ is halo, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl whereinthe aliphatic, alicyclic and aromatic groups in E are optionallysubstituted with one, two, or three R^(a) independently selected fromhydroxy, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, alkylthio,arylthio, heteroarylthio, amino, monosubstituted amino, disubstitutedamino, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl,alkenyloxycarbonyl, alkynyloxycarbonyl, alkenylaminocarbonyl, acylamino,aminocarbonyl, halo, or cyano and further wherein the aromatic oralicyclic ring in R^(a) is optionally substituted with one, two, orthree substituents independently selected from alkyl, alkoxy, halo,haloalkyl, haloalkoxy, carboxy, or carboxyalkyl; and optionally, R⁵ andR⁶, and R¹¹ and R¹² can be combined with the nitrogen to which they areattached to form a five- to seven-membered ring;

R¹ is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl orheterocyclylalkyl wherein the aliphatic, alicyclic and aromatic groupsin R¹ are optionally substituted with one or two R^(b) independentlyselected from hydroxy, alkoxy, aryloxy, heteroaryloxy, alkylthio,arylthio, heteroarylthio, amino, monosubstituted amino, disubstitutedamino, alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, acylamino,aminocarbonyl, halo, or cyano and further wherein the aromatic oralicyclic ring in R^(b) is optionally substituted with one, two, orthree substituents independently selected from alkyl, alkoxy, halo,haloalkyl, haloalkoxy, cyano, carboxy, or carboxyalkyl;

X is —O—, —NR¹⁴—, —S—, —SO—, or —SO₂—;

R³ is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl orheterocyclylalkyl wherein the aliphatic, alicyclic and aromatic groupsin R³ are optionally substituted with one or two R^(c) independentlyselected from hydroxy, alkoxy, haloalkoxy, aryloxy, heteroaryloxy,alkylthio, arylthio, heteroarylthio, amino, monosubstituted amino,disubstituted amino, alkylsulfonyl, arylsulfonyl, carboxy,alkoxycarbonyl, acylamino, aminocarbonyl, halo, or cyano and furtherwherein the aromatic or alicyclic ring in R^(c) is optionallysubstituted with one, two, or three substituents independently selectedfrom alkyl, alkoxy, halo, haloalkyl, haloalkoxy, carboxy, orcarboxyalkyl;

Y is —C(O)NH—, —OC(O)NH—, —NR¹⁴—C(O)NH—, or —NR¹⁴C(O)O—. For each of Xand Y, each R¹⁴ when present is independently selected from hydrogen,alkyl optionally substituted with halo, hydroxy, alkoxy, amino,monosubstituted amino, disubstituted amino and aryl, heteroaryl orheterocyclyl, each of which is optionally substituted with halo andalkyl;

R² is heteroaryl or —CO-(fused heterocyclyl) ring wherein the heteroaryland fused heterocyclyl rings are optionally substituted with one, two,three, or four R^(d) independently selected from hydrogen, alkyl,cycloalkyl, alkenyl, alkynyl, alkylthio, hydroxy, alkoxy, halo,haloalkyl, haloalkoxy, carboxy, carboxyalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, alkylsulfonyl, alkylcarbonyl, aryl, aralkyl, arylsulfonyl,arylcarbonyl, aryloxycarbonyl, aminosulfonyl, aminocarbonyl, heteroaryl,heteroaralkyl, heteroarylsulfonyl, heteroarylcarbonyl,heteroaryloxycarbonyl, heterocyclyl, heterocyclylalkyl,heterocyclylsulfonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,amino, monosubstituted amino, or disubstituted amino or when two R^(d)are on adjacent carbon atoms they together with the carbon atoms towhich they are attached form a four, five or six membered heterocyclylring containing one or two heteroatoms selected from nitrogen, oxygen,sufur, or —SO₂— wherein the heterocyclyl ring is optionally substitutedwith one or two alkyl; and further wherein the aromatic or alicyclicring in R^(d) is optionally substituted with one, two, or three R^(e)independently selected from alkyl, alkylcarbonylamino,alkoxycarbonylamino, cycloalkyl, cycloalkylalkyl,cycloalkoxycarbonylamino, cycloalkylalkyloxycarbonylamino, nitro,alkoxy, cycloalkyloxy, aryloxy, heteroaryloxy, halo, haloalkyl,haloalkoxy, hydroxyl, carboxy, alkoxycarbonyl, amino, monosubstitutedamino, disubstituted amino, acylamino, or ureido wherein cycloalkyl andcycloalkylalkyl in R^(e) are optionally substituted with one, two orthree alkyl; and

R⁴ is:

-   -   (i) alkyl provided that Y is —OC(O)NH—, —NR¹⁴—C(O)NH—, or        —NR¹⁴C(O)O— and when R² is heteroaryl then at least one of R^(d)        is not hydrogen;    -   (ii) cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, heterocyclyl, or heterocyclylalkyl provided that        the heteroaryl and fused heterocyclyl ring in R² are substituted        with at least a heteroaryl ring; or    -   (iii) alkyl provided that when Y is —C(O)NH— or —SO₂NH— then the        heteroaryl and fused heterocyclyl rings in R² are substituted        with at least a heteroaryl ring;        wherein the aromatic or alicyclic ring in R⁴ is optionally        substituted with one, two, or three R^(f) independently selected        from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, carboxy,        carboxyalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,        alkylsulfonyl, alkylcarbonyl, aryl, aralkyl, arylsulfonyl,        arylcarbonyl, aryloxycarbonyl, aminosulfonyl, aminocarbonyl,        heteroaryl, heteroaralkyl, heteroarylsulfonyl,        heteroarylcarbonyl, heteroaryloxycarbonyl, heterocyclyl,        heterocyclylalkyl, heterocyclylsulfonyl, heterocyclylcarbonyl,        heterocyclyloxycarbonyl, monosubstituted amino, or disubstituted        amino wherein the aromatic or alicyclic ring in R^(f) is        optionally substituted with one, two, or three substituents        independently selected from alkyl, alkoxy, halo, haloalkyl,        haloalkoxy, hydroxy, carboxy, alkoxycarbonyl, monosubstituted        amino, disubstituted amino, or acylamino; or a pharmaceutically        acceptable salts thereof.

For the sake of clarity, it is pointed out that the point of attachmentof the Y groups to the R⁴ group as follows: R⁴C(O)NH—, R⁴OC(O)NH—,R⁴NR¹⁴—C(O)NH—, or R⁴NR¹⁴C(O)O—.

In a second aspect, this invention is directed to a pharmaceuticalcomposition comprising a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in admixture with one or more pharmaceuticallyacceptable excipient.

In a third aspect, this invention is directed to a method for treatinghepatitis C in an animal which method comprises administering to theanimal a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in admixture with one or more pharmaceuticallyacceptable excipient.

In a fourth aspect, this invention is directed to processes forpreparing compounds of Formula (I).

BRIEF DESCRIPTION OF THE DRAWINGS

Not applicable

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this Application and have thefollowing meanings.

“Alicyclic” means a moiety characterized by arrangement of the carbonatoms in closed non-aromatic ring structures e.g., cycloalkyl andheterocyclyl rings as defined herein.

“Aliphatic” means alkyl, alkenyl, or alkynyl radicals as defined herein

“Alkyl” represented by itself means a straight or branched, saturatedaliphatic radical containing one to eight carbon atoms, unless otherwiseindicated e.g., alkyl includes methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, and the like.

“Alkylcarbonylamino” refers to a —NHC(O)R radical where R is an alkylgroup as defined above e.g., methylcarbonylamino, ethylcarbonylamino,and the like.

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated aliphatic, divalent radical having the number of one to sixcarbon atoms, e.g., methylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene(—CH₂CH₂CH₂—), tetramethylene (—CH₂CH₂CH₂CH₂—) 2-methyltetramethylene(—CH₂CH(CH₃)CH₂CH₂—), pentamethylene (—CH₂CH₂CH₂CH₂CH₂—), and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms containing one or two double bonds e.g., ethenyl,propenyl (including all isomeric forms), 1-methylpropenyl, butenyl(including all isomeric forms), or pentenyl (including all isomericforms), and the like.

“Alkenyloxycarbonyl” refers to a —C(O)OR radical where R is an alkenylgroup as defined above e.g., 3-propen-1-yloxycarbonyl, and the like.

“Alkenylaminocarbonyl” refers to a —C(O)NHR radical where R is analkenyl group as defined above e.g., 3-propen-1-ylaminocarbonyl, and thelike.

“Alklynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms containing one or two triple bonds e.g., ethynyl,propynyl (including all isomeric forms), 1-methylpropynyl, butynyl(including all isomeric forms), or pentynyl (including all isomericforms), and the like.

“Alkynyloxycarbonyl” refers to a —C(O)OR radical where R is an alkynylgroup as defined above e.g., 3-propyn-1-yloxycarbonyl, and the like.

“Alkylthio” means an —SR radical where R is alkyl as defined herein,e.g., methylthio, ethylthio, propylthio, or butylthio, and the like.

“Alkylsulfonyl” means —SO₂R radical where R is alkyl as defined hereine.g., methylsulfonyl, ethylsulfonyl, and the like.

“Alkoxy” refers to a —OR radical where R is an alkyl group as definedabove e.g., methoxy, ethoxy, and the like.

“Alkoxycarbonylamino” refers to a —NHC(O)OR radical where R is an alkylgroup as defined above e.g., methoxycarbonylamino, ethoxycarbonylamino,and the like.

“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with at least one alkoxy group, preferablyone or two alkoxy groups, as defined above, e.g., 2-methoxy-ethyl, 1-,2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

“Alkoxycarbonyl” refers to a —C(O)OR radical where R is an alkyl groupas defined above e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

“Amino” means a —NH₂ radical.

“Alkylamino” means a radical —NHR where R is alkyl as defined herein,e.g., methylamino, ethylamino, n-, iso-propylamino, n-, iso-,tert-butylamino, and the like.

“Aminoalkyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbons substituted with at least one, preferably one or two, —NRR′where R is hydrogen, alkyl, acyl, hydroxyalkyl, alkoxyalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl or heterocyclylalkyl and R′ ishydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl,aminocarbonyl, or aminosulfonyl as defined herein e.g., aminomethyl,methylaminoethyl, dimethylaminoethyl, 1,3-diaminopropyl,acetylaminopropyl, and the like.

“Acyl” refers to a —COR radical where R is hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclyl asdefined herein, e.g., formyl, acetyl, trifluoroacetyl, benzoyl,piperazin-1-ylcarbonyl, and the like. When R is alkyl it is referred toin this application as alkylcarbonyl. When R is aryl it is referred toin this application as arylcarbonyl. When R is heteroaryl it is referredto in this application as heteroarylcarbonyl. When R is heterocyclyl itis referred to in this application as heterocyclylcarbonyl.

“Acylamino” refers to a —NRCOR′ radical where R is hydrogen or alkyl andR′ is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, or heterocyclyl as defined herein, e.g., formyl, acetyl,trifluoroacetyl, benzoyl, piperazin-1-ylcarbonyl, and the like.

“Aminocarbonyl” means —CONRR′ radical where R and R′ are independentlyselected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,or heterocyclylalkyl or R and R′ together with the nitrogen atom towhich they are attached form heterocycloamino as defined herein.

“Aminosulfonyl” means —SO₂NRR′ radical where R and R′ are independentlyselected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,or heterocyclylalkyl or R and R′ together with the nitrogen atom towhich they are attached form heterocycloamino as defined herein.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” refers to a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp² hybridizedand the total number of pi electrons is equal to 4n+2.

“Aryl” refers to a monocyclic or fused bicyclic ring assembly containing6 to 10 ring carbon atoms wherein each ring is aromatic e.g., phenyl ornaphthyl.

“Aryloxy” refers to a —O—R radical where R is aryl as defined abovee.g., phenoxy, napthyloxy, and the like.

“Aryloxycarbonyl” refers to a —C(O)OR radical where R is aryl as definedabove e.g., phenyloxycarbonyl, naphthyloxycarbonyl, and the like.

“Aralkyl” refers to a -(alkylene)-R radical where R is aryl as definedabove e.g., benzyl, phenethyl, and the like.

“Arylthio” means an —SR radical where R is aryl as defined herein, e.g.,phenylthio or naphthylthio.

“Arylsulfonyl” means an —SO₂R radical where R is aryl as defined herein,e.g., phenylsulfonyl or naphthylsulfonyl.

“Carboxy” refers to —C(O)OH radical.

“Carboxyalkyl” means an alkyl radical, as defined herein, substitutedwith at least one, preferably one or two, —C(O)OH group(s), e.g.,carboxymethyl, carboxyethyl, 1-, 2-, or 3-carboxypropyl, and the like.

“Cycloalkyl” refers to a monovalent saturated monocyclic ring containingthree to eight ring carbon atoms e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

“Cycloalkylalkyl” refers to a -(alkylene)-R radical where R iscycloalkyl as defined above e.g., cyclopropylmethyl, cyclobutylethyl,cyclobutylmethyl, and the like.

“Cycloalkyloxy” refers to a —OR radical where R is cycloalkyl as definedabove e.g., cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

“Cycloalkyloxycarbonylamino” refers to a —NHC(O)OR radical where R iscycloalkyl as defined above e.g., cyclopropyloxycarbonylamino,cyclopentyloxycarbonylamino, and the like.

“Cycloalkylalkyloxycarbonylamino” refers to a —NHC(O)OR radical where Ris cycloalkylalkyl as defined above e.g.,cyclopropylmethyloxycarbonylamino, cyclopentylmethyloxycarbonylamino,and the like.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Dialkylamino” means a radical —NRR′ where R and R′ are iridependentlyalkyl as defined herein, e.g., dimethylamino, diethylamino,N,N-methylpropylamino or N,N-methylethylamino, and the like.

“Disubstituted amino” means a radical —NRR′ where R and R′ areindependently selected from alkyl, cycloalkyl, cycloalkylalkyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl as defined herein, e.g., dimethylamino, diethylamino,N,N-methylpropylamino or N,N-methylethylamino, methylphenylamino, andthe like. Dialkylamino is a subgroup of disubstituted amino.

“Fused heterocyclyl” means heterocyclyl radical as defined herein thatis fused to an aryl or heteroaryl ring as defined herein e.g.,2,3-dihydroisoindol-1-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl, and thelike.

“Halo” refers to fluoro, chloro, bromo or iodo.

“Haloalkyl” refers to alkyl as defined above substituted by one or more,preferably one to seven, “halo” atoms, as such terms are defined in thisApplication. Haloalkyl includes monohaloalkyl, dihaloalkyl,trihaloalkyl, perhaloalkyl and the like e.g. chloromethyl,dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like.

“Haloalkoxy” refers to a —OR radical where R is haloalkyl group asdefined above e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy,difluoromethoxy, and the like.

“Heteroaryl” as a group or part of a group denotes an aromaticmonocyclic or bicyclic moiety of 5 to 10 ring atoms in which one ormore, preferably one, two, or three, of the ring atom(s) is(are)selected from nitrogen, oxygen or sulfur, the remaining ring atoms beingcarbon. Representative heteroaryl rings include, but are not limited to,pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, pyrazolyl, and the like.

“Heteroaryloxy” refers to a —O—R radical where R is heteroaryl asdefined above e.g., furanyloxy, pyridinyloxy, indolyloxy, and the like.

“Heteroaryloxycarbonyl” refers to a —C(O)O—R radical where R isheteroaryl as defined above e.g., pyridinyloxycarbonyl,pyrimidinyloxycarbonyl, and the like.

“Heteroaralkyl” refers to a -(alkylene)-R radical where R is heteroarylas defined above e.g., pyridinylmethyl, 1- or 2-furanylethyl,imidazolylmethyl, and the like.

“Heteroaralkyloxycarbonyl” refers to a —C(O)O—R radical where R isheteroaralkyl as defined above e.g., pyridinylmethyloxycarbonyl,pyrimidinylmethyloxycarbonyl, and the like.

“Heteroarylthio” means an —SR radical where R is heteroaryl as definedherein, e.g., pyridinylthio, furanylthio, thienylthio, and the like.

“Heteroarysulfonyl” means an —SO₂R radical where R is heteroaryl asdefined herein, e.g., pyridinylsulfonyl, thienylsulfonyl, and the like.

“Heterocyclyl” refers to a saturated or partially unsaturated, mono orbicyclic radical of 4, 5, 6, or 7 carbon ring atoms wherein one or more,preferably one, two, or three of the ring carbon atoms are replaced by aheteroatom selected from —N═, —N—, —O—, —S—, —SO—, or —S(O)₂— andfurther wherein one or two ring carbon atoms are optionally replaced bya keto (—CO—) group. The heterocyclyl ring is optionally fused tocycloalkyl, aryl or heteroaryl ring as defined herein. Representativeexamples include, but are not limited to, imidazolidinyl, morpholinyl,thiomorpholinyl, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl,1-oxo-tetrahydrothiopyranyl, 1,1-dioxotetrathio-pyranyl, indolinyl,piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl,quinuclidinyl,3,4-dihydroisoquinolinyl, dihydroindolyl, and the like.When the heterocyclyl group contains at least one nitrogen ring atom itis referred to herein as “heterocycloamino” and is a subset of theheterocyclyl group as defined above.

“Heterocyclylalkyl” refers to a -(alkylene)-R radical where R isheterocyclyl as defined above e.g., pyrrolidinylmethyl,tetrahydrofuranylethyl, pyridinylmethylpiperidinylmethyl, and the like.

“Heterocyclyloxycarbonyl” refers to a —C(O)OR radical where R isheterocyclyl as defined above e.g., piperidinyloxycarbonyl,tetrahydrofuranoxycarbonyl, and the like.

“Heterocyclylsulfonyl” means an —SO₂R radical where R is heterocyclyl asdefined herein, e.g., piperidin-1-ylsulfonyl, pyrrolidin-1-ylsulfonyl,and the like.

“Hydroxy” means —OH radical.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with one or two hydroxy groups, provided thatif two hydroxy groups are present they are not both on the same carbonatom. Representative examples include, but are not limited to,hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

“Isomers” mean compounds of Formula (I) having identical molecularformulae but differ in the nature or sequence of bonding of their atomsor in the arrangement of their atoms in space. Isomers that differ inthe arrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers”. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”. A compound with one chiral center that has two enantiomericforms of opposite chirality is termed a “racemic mixture”. A compoundthat has more than one chiral center has 2^(n−1) enantiomeric pairs,where n is the number of chiral centers. Compounds with more than onechiral center may exist as either an individual diastereomer or as amixture of diastereomers, termed a “diastereomeric mixture”. When onechiral center is present a stereoisomer may be characterized by theabsolute configuration of that chiral center. Absolute configurationrefers to the arrangement in space of the substituents attached to thechiral center. Enantiomers are characterized by the absoluteconfiguration of their chiral centers and described by the R- andS-sequencing rules of Cahn, Ingold and Prelog. Conventions forstereochemical nomenclature, methods for the determination ofstereochemistry and the separation of stereoisomers are well known inthe art (e.g., see “Advanced Organic Chemistry”, 4th edition, March,Jerry, John Wiley & Sons, New York, 1992). It is understood that thenames and illustration used in this Application to describe compounds ofFormula (I) are meant to encompass all possible stereoisomers.

“Monosubstituted amino” means a radical —NHR where R is selected fromalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl as definedherein, e.g., methylamino, ethylamino, propylamino, phenylamino,benzylamino, and the like.

“Optional” or “optionally” or “may be” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, the phrase “wherein thearomatic ring in R^(a) is optionally substituted with one or twosubstituents independently selected from alkyl” means that the aromaticring may or may not be substituted with alkyl in order to fall withinthe scope of the invention.

The present invention also includes N-oxide derivatives of a compound ofFormula (I). N-oxide derivative mean a compound of Formula (I) in whicha nitrogen atom is in an oxidized state (i.e., N→O) e.g., pyridineN-oxide, and which possess the desired pharmacological activity.

“Pathology” of a disease means the essential nature, causes anddevelopment of the disease as well as the structural and functionalchanges that result from the disease processes.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of Formula(I) which are pharmaceutically acceptable, as defined above, and whichpossess the desired pharmacological activity. Such salts include acidaddition salts formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or with organic acids such as acetic acid, propionic acid,hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methylsulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxy-ethanesulfonic acid, benzenesulfonic acid,p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

The present invention also includes prodrugs of a compound of Formula(I). Prodrug means a compound that is convertible in vivo by metabolicmeans (e.g. by hydrolysis) to a compound of Formula (I). For example, anester of a compound of Formula (I) containing a hydroxy group may beconvertible by hydrolysis in vivo to the parent molecule. Alternativelyan ester of a compound of Formula (I) containing a carboxy group may beconvertible by hydrolysis in vivo to the parent molecule. Suitableesters of compounds of Formula (I) containing a hydroxy group, are forexample acetates, citrates, lactates, tartrates, malonates, oxalates,salicylates, propionates, succinates, fumarates, maleates,methylene-bis-βb-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methylsulphonates, ethanesulphonates,benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates andquinates. Suitable esters of compounds of Formula (I) containing acarboxy group, are for example those described by Leinweber, F. J. DrugMetab. Res., 1987, 18, page 379. An especially useful class of esters ofcompounds of Formula (I) containing a hydroxy group, may be formed fromacid moieties selected from those described by Bundgaard et al., J. Med.Chem., 1989, 32, pp 2503-2507, and include substituted(aminomethyl)-benzoates, for example, dialkylamino-methylbenzoates inwhich the two alkyl groups may be joined together and/or interrupted byan oxygen atom or by an optionally substituted nitrogen atom, e.g. analkylated nitrogen atom, more especially (morpholino-methyl)benzoates,e.g. 3- or 4-(morpholinomethyl)-benzoates, and(4-alkylpiperazin-1-yl)benzoates, e.g. 3- or4-(4-alkylpiperazin-1-yl)benzoates. It is understood that the names andillustration used in this Application to describe compounds of Formula(I) are meant to be encompassed all possible prodrugs thereof.

“Protected derivatives” means derivatives of compounds of Formula (I) inwhich a reactive site or sites are blocked with protecting groups.Protected derivatives of compounds of Formula (I) are useful in thepreparation of compounds of Formula (I) or in themselves may be activecathepsin S inhibitors. A comprehensive list of suitable protectinggroups can be found in T. W. Greene, Protective Groups in OrganicSynthesis, 3rd edition, John Wiley & Sons, Inc. 1999. It is understoodthat the names and illustration used in this Application to describecompounds of Formula (I) are meant to be encompassed all possibleprotected derivatives thereof.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

-   -   (1) preventing the disease from occurring in an animal which may        be predisposed to the disease but does not yet experience or        display the pathology or symptomatology of the disease,    -   (2) inhibiting the disease in an animal that is experiencing or        displaying the pathology or symptomatology of the diseased        (i.e., arresting further development of the pathology and/or        symptomatology), or    -   (3) ameliorating the disease in an animal that is experiencing        or displaying the pathology or symptomatology of the diseased        (i.e., reversing the pathology and/or symptomatology).

“Ureido” means a radical —NHCONRR′ where R is hydrogen or alkyl and R′is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl.

PREFERRED EMBODIMENTS

Certain compounds of Formula (I) within the broadest scope set forth inthe Summary of the Invention are preferred. For example:

A. A preferred group of compounds of Formula (I) is that wherein:

E is —COCONHR⁶ where R⁶ is hydrogen, alkyl, cycloalkyl, aralkyl, orheteroaralkyl wherein the aromatic ring is optionally substituted withone or two halo, preferably, R⁶ is cyclopropyl, —CH(CH₃)R where R isphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,3,4-dichlorophenyl, 3,4-difluorophenyl, or pyridin-4-yl. Preferably, R⁶is cyclopropyl.

B. Another preferred group of compounds of Formula (I) is that wherein:

E is —COCOOR¹⁰ where R¹⁰ is as defined in the Summary of the Invention.Preferably, R¹⁰ is —CH₂C≡CH, —CH₂CH═CH₂, n-propyl, 2,2-dimethylpropyl,carboxymethyl, methoxycarbonylmethyl, tert-butoxycarbonylmethyl,—CH₂C(O)OCH₂C≡CH, —CH₂C(O)OCH₂CH═CH₂, —CH₂C(O)O(CH₂)₂CH₃, —CH₂C(O)NH₂,—CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂, —CH₂C(O)NHCH₂CH═CH₂, or 2-phenethyl.

(a) Within the above preferred groups A and B and more preferred groupscontained therein, a more preferred group of compounds is that wherein:

X is —O—;

R¹ is alkyl optionally substituted with alkoxy, alkylthio oralkylsulfonyl, alkenyl, alkynyl, cycloalkyl, or cycloalkylalkyl,preferably methyl, ethyl, n-propyl, n-butyl, n-pentyl, prop-2-enyl,propyn-2-yl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl,3-methylbutyl, cyclopropyl, methoxymethyl, 2-methoxyethyl,methylthiomethyl, methylsulfonylmethyl, or cyclobutylmethyl. Morepreferably, cyclobutylmethyl, ethyl, n-propyl or n-butyl; and

R³ is alkyl, cycloalkyl, or aryl, more preferably, 1-methylethyl,1-methylpropyl, tert-butyl, cyclopropyl, phenyl, or cyclohexyl.Preferably, R³ is tert-butyl or cyclohexyl.

(1) Within the groups (A), (B), A(a), and B(a) and more preferred groupscontained therein, a more preferred group of compounds is that wherein:

-   Y is —OC(O)NH—; R² is heteroaryl optionally substituted with one,    two, three, or four R^(d) independently selected from hydrogen,    alkyl, cycloalkyl, alkynyl, alkylthio, hydroxy, alkoxy, halo,    haloalkyl, haloalkoxy, carboxy, carboxyalkyl, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylcarbonyl, aryl,    aralkyl, arylsulfonyl, arylcarbonyl, aryloxycarbonyl, aminosulfonyl,    aminocarbonyl, heteroaryl, heteroaralkyl, heteroarylsulfonyl,    heteroarylcarbonyl, heteroaryloxycarbonyl, heterocyclyl,    heterocyclylalkyl, heterocyclylsulfonyl, heterocyclylcarbonyl,    heterocyclyloxycarbonyl, amino, monosubstituted amino, or    disubstituted amino or when two R^(d) are on adjacent carbon atoms    they, together with the carbon atoms to which they are attached,    form a four, five or six membered heterocyclyl ring containing one    or two heteroatoms selected from nitrogen, oxygen, sufur, or —SO₂—    wherein the heterocyclyl ring is optionally substituted with one or    two alkyl; and further wherein the aromatic or alicyclic ring in    R^(d) is optionally substituted with one, two, or three R^(e)    independently selected from alkyl, alkoxycarbonylamino, cycloalkyl,    cycloalkylalkyl, cycloalkoxycarbonylamino,    cycloalkylalkyloxycarbonylamino, nitro, alkoxy, cycloalkyloxy,    aryloxy, heteroaryloxy, halo, haloalkyl, haloalkoxy, hydroxyl,    carboxy, alkoxycarbonyl, monosubstituted amino, disubstituted amino,    acylamino, or ureido wherein the cycloalkyl and cycloalkylalkyl in    R^(e) are optionally substituted with one, two or three alkyl; and-   R⁴ is alkyl, preferably tert-butylmethyl provided that at least one    of R^(d) is not hydrogen.

(i) Preferably, R² is a group of formula (a):

where:

-   R^(d1) is hydrogen, hydroxy, alkoxy, amino, alkylamino,    dialkylamino, haloalkoxy or alkylsulfonyl;-   R^(d) and R^(d2) are independently hydrogen, alkyl, halo, alkoxy,    alkylthio, or alkylsulfonyl; or-   R^(d1) and R^(d) or R^(d1) and R^(d2) togeether with the carbon    atoms to which they are attached form 4, 5, or 6-atom heterocyclyl    ring wherein one or two ring atoms are replaced by oxygen or —N—    where the heterocyclyl ring is optionally substituted with one or    two alkyl;-   R^(d3) is aryl, heteroaryl, cycloalkyl or heterocyclyl optionally    substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,    cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino,    cycloalkylalkylcarbonylamino, alkoxycarbonylamino, amino,    alkylamino, dialkylamino, cycloalkylamino, cycloalkylalkylamino, or    —NHCONRR′ where R is hydrogen or alkyl and R′ is hydrogen, alkyl,    cycloalkyl, or cycloalkylalkyl wherein cycloalkyl and    cycloalkylalkyl in R^(d3) are optionally substituted with one, two    or three alkyl.

Preferably,

-   R^(d1) is hydrogen, hydroxy, alkoxy, amino, alkylamino or    dialkylamino;-   R^(d) and R^(d2) are independently hydrogen, alkyl, halo, alkoxy,    alkylthio, or alkylsulfonyl; and-   R^(d3) is a group of formula:

optionally substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl,alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino,cycloalkylalkylcarbonylamino, alkyloxycarbonylamino, amino, alkylamino,dialkylamino, cycloalkylamino, cycloalkylalkylamino, or —NHCONRR′ whereR is hydrogen or alkyl and R′ is hydrogen, alkyl, cycloalkyl, orcycloalkylalkyl wherein cycloalkyl and cycloalkylalkyl are optionallysubstituted with one, two or three alkyl.

More preferably, R^(d3) is a group of formula:

optionally substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl,alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino,cycloalkylalkylcarbonylamino, alkyloxycarbonylamino, amino, alkylamino,dialkylamino, cycloalkylamino, cycloalkylalkylamino, or —NHCONRR′ whereR is hydrogen or alkyl and R′ is hydrogen, alkyl, cycloalkyl, orcycloalkylalkyl wherein cycloalkyl and cycloalkylalkyl are optionallysubstituted with one, two or three alkyl.

Even more preferably, R^(d3) is:

optionally substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl,alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino,cycloalkylalkylcarbonylamino, alkyloxycarbonylamino, amino, alkylamino,dialkylamino, cycloalkylamino, cycloalkylalkylamino, or —NHCONRR′ whereR is hydrogen or alkyl and R′ is hydrogen, alkyl, cycloalkyl, orcycloalkylalkyl wherein cycloalkyl and cycloalkylalkyl are optionallysubstituted with one, two or three alkyl.

In still other preferred embodiments of subgroup (i), R^(d3) iscycloalkyl, more preferably cyclopropyl, cyclobutyl or cyclopentyl,still more preferably, cyclopropyl. The remaining groups, R^(d), R^(d1)and R^(d2) have the meanings provided for formula (a).

Within the above preferred groups, a more preferred group of compoundsis that wherein:

-   R^(d1) is hydrogen, hydroxy, methoxy, ethoxy, n-propoxy,    iso-propoxy, methylamino, ethylamino, n-propylamino, isopropylamino,    dimethylamino, methylethylamino, methyl(n-propyl)amino and    methyl(isopropyl)amino; more preferably, hydrogen hydroxyl; methoxy    or dimethylamino, even more preferably methoxy. Alternatively, even    more preferably hydrogen;-   R^(d) and R^(d2) are independently, hydrogen, fluoro, chloro,    methyl, ethynyl, methoxy, ethoxy, methylthio or methylsulfonyl. More    preferably, R^(d) is hydrogen, ethynyl, fluoro, chloro, methyl,    methoxy, methylthio or methylsulfonyl and R^(d2) is hydrogen.

Most preferably, R^(d1) is methoxy, R^(d) is hydrogen or methyl, fluoro,chloro, or methoxy and R^(d2) is hydrogen.

(ii) Preferably, R² is a group of formula:

where:

-   Z^(a) and Z^(b) are independently —O— or —NH— where H can be    replaced by R, preferably Z^(a) and Z^(b) are —O—;-   R is alkyl, preferably methyl;-   R^(d2) is hydrogen or methyl, preferably hydrogen; and-   R^(d3) is as defined for subgroup (i) immediately above.

(iii) Preferably, R² is a group of formula:

Z^(a) and Z^(b) are independently —O— or —NH— where H can be replaced byR, preferably Z^(a) and Z^(b) are —O—;

-   R is alkyl, preferably methyl;-   R^(d) is hydrogen or methyl, preferably hydrogen; and-   R^(d3) is as defined for subgroup (i) immediately above.

(iv) Preferably, R² is a group of formula (b):

where:

-   R^(d1) is hydrogen, hydroxy, alkoxy, amino, alkylamino,    dialkylamino, haloalkoxy or alkylsulfonyl;-   R^(d) and R^(d2) are independently hydrogen, alkyl, halo, alkoxy,    alkylthio, or alkylsulfonyl; or-   R^(d1) and R^(d) or R^(d1) and R^(d2) together with the carbon atoms    to which they are attached form 4, 5, or 6-atom heterocyclyl ring    wherein one or two ring atoms are replaced by oxygen or —N— where    the heterocyclyl ring is optionally substituted with one or two    alkyl;-   R^(d3) is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl.

Preferably,

-   R^(d1) is hydrogen, hydroxy, alkoxy, amino, alkylamino or    dialkylamino;-   R^(d) and R^(d2) are independently hydrogen, alkyl, halo, alkoxy,    alkylthio, or alkylsulfonyl; and-   R^(d3) is hydrogen, alkyl or cycloalkyl.

Within the above preferred groups, a more preferred group of compoundsis that wherein:

-   R^(d1) is hydrogen, hydroxy, methoxy, ethoxy, n-propoxy,    iso-propoxy, methylamino, ethylamino, n-propylamino, isopropylamino,    dimethylamino, methylethylamino, methyl(n-propyl)amino and    methyl(isopropyl)amino; more preferably, hydrogen, hydroxyl,    methoxy, ethoxy or dimethylamino, even more preferably methoxy or    ethoxy; and-   R^(d) and R^(d2) are independently, hydrogen, fluoro, chloro,    methyl, ethynyl, methoxy, ethoxy, methylthio or methylsulfonyl; more    preferably, R^(d) is hydrogen, ethynyl, fluoro, chloro, methyl,    methoxy, methylthio or methylsulfonyl and R^(d2) is hydrogen.

Most preferably, R^(d1) is methoxy or ethoxy, R^(d) is hydrogen ormethyl, fluoro, chloro, or methoxy and R^(d2) is hydrogen.

Within the above groups (i)-(iii), and more preferred groups containedtherein, a more preferred group of compounds is that wherein the R^(d3)rings are optionally substituted with methyl, ethyl, n-propyl, i-propyl,n-butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, 2,2,dimethylpropyl,1,2-dimethylpropyl, 1,2,2-trimethylpropyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl and cyclohexylmethyl each of said cycloalkyl andcycloalkylalkyl rings being optionally substituted with one to threesubstitutents independently selected from methyl or ethyl, preferablymethyl.

Within the above groups (i)-(iii), and more preferred groups containedtherein, a more preferred group of compounds is that wherein the R^(d3)rings are optionally substituted with amino, methylamino, ethylamino,propylaamino, 1-methylethylamino, 1,1-dimethylethylamino,2-methylpropylamino, 1-methylpropylamino, 2,2-dimethylpropylamino,1,2-dimethylpropylamino, 1,1-dimethylpropylamino, cyclopropylamino,cyclobutylamino, cyclopentylamino, cyclohexylamino,cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino,cyclohexylmethylamino, methylcarbonylamino, ethylcarbonylamino,propylcarbonylamino, 1-methylethylcarbonylamino,1,1-dimethylethylcarbonylamino, 2-methylpropylcarbonylamino,1-methylpropylcarbonylamino, 2,2-dimethylpropylcarbonylamino,1,2-dimethylpropylcarbonylamino, 1,1-dimethylpropylcarbonylamino,cyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopentylcarbonylamino, cyclohexylcarbonylamino,cyclopropylmethylcarbonylamino, cyclobutylmethylcarbonylamino,cyclopentylmethylcarbonylamino, cyclohexylmethylcarbonylamino,methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylaamino,1-methylethoxycarbonylamino, 1,1-dimethyl-ethoxycarbonylamino,2-methylpropoxycarbonylamino, 1-methylpropoxycarbonylamino,2,2-dimethylpropoxycarbonylamino, 1,2-dimethylpropoxylcarbonylamino, or1,1-dimethylpropoxy-carbonylamino.

(2) Within the groups (A), (B), A(a), and B(a) and more preferred groupscontained therein, a more preferred group of compounds is that wherein:

-   Y is —NHC(O)NH—, R² is as defined in preferred embodiment (1) above,    including the preferred subgroups thereof, and R⁴ is alkyl,    preferably tert-butyl.

(3) Within the groups (A), (B), A(a), and B(a) and more preferred groupscontained therein, a more preferred group of compounds is that wherein:

-   Y is —C(O)NH—, R² is as defined in preferred embodiment (1) above,    including the preferred subgroups thereof provided that R^(d3) is a    heteroaryl ring, and R⁴ is as defined in the Summary of the    Invention, preferably alkyl, more preferably tert-butyl.

(4) Within the groups (A), (B), A(a), and B(a) and more preferred groupscontained therein, a more preferred group of compounds is that wherein:

-   Y is —OC(O)NH—, R² is —CO-(fused heterocyclyl) wherein the fused    heterocyclyl is optionally substituted with one, two, or three R^(d)    independently selected from alkyl, alkoxy, halo, haloalkyl,    haloalkoxy, carboxy, carboxyalkyl, hydroxyalkyl, alkoxyalkyl,    aminoalkyl, alkylsulfonyl, alkylcarbonyl, aryl, aralkyl,    arylsulfonyl, arylcarbonyl, aryloxycarbonyl, aminosulfonyl,    aminocarbonyl, heteroaryl, heteroaralkyl, heteroarylsulfonyl,    heteroarylcarbonyl, heteroaryloxycarbonyl, heterocyclyl,    heterocyclylalkyl, heterocyclylsulfonyl, heterocyclylcarbonyl,    heterocyclyloxycarbonyl, monosubstituted amino, or disubstituted    amino wherein the aromatic or alicyclic ring in R^(d) is optionally    substituted with one, two, or three R^(e) independently selected    from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, carboxy,    alkoxycarbonyl, monosubstituted amino, disubstituted amino, or    acylamino; and R⁴ is alkyl. Preferably, R² is    2,3-dihydroisoindol-1-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl    substituted with one, two, or three R^(d) listed immediately above.

(5) Within the groups (A), (B), A(a), and B(a) and more preferred groupscontained therein, a more preferred group of compounds is that wherein:

-   Y is —NHC(O)NH—, R² is —CO-(fused heterocyclyl) wherein the fused    heterocyclyl is substituted with one, two, or three R^(d)    independently selected from alkyl, alkoxy, halo, haloalkyl,    haloalkoxy, carboxy, carboxyalkyl, hydroxyalkyl, alkoxyalkyl,    aminoalkyl, alkylsulfonyl, alkylcarbonyl, aryl, aralkyl,    arylsulfonyl, arylcarbonyl, aryloxycarbonyl, arninosulfonyl,    aminocarbonyl, heteroaryl, heteroaralkyl, heteroarylsulfonyl,    heteroarylcarbonyl, heteroaryloxycarbonyl, heterocyclyl,    heterocyclylalkyl, heterocyclylsulfonyl, heterocyclylcarbonyl,    heterocyclyloxycarbonyl, monosubstituted amino, or disubstituted    amino wherein the aromatic or alicyclic ring in R^(d) is optionally    substituted with one, two, or three R^(e) independently selected    from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyl, carboxy,    alkoxycarbonyl, monosubstituted amino, disubstituted amino, or    acylamino; and R⁴ is alkyl. Preferably, R² is    2,3-dihydroisoindol-1-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl    optionally substituted with one, two, or three R^(d) listed    immediately above.

(C) Yet another preferred group of compounds of Formula (I) is thatwherein R² is a group of formula (a):

where:

-   R^(d1) is hydrogen, hydroxy, alkoxy, amino, alkylamino,    dialkylamino, haloalkoxy or alkylsulfonyl;-   R^(d) and R^(d2) are independently hydrogen, alkyl, halo, alkoxy,    alkylthio, or alkylsulfonyl; or-   R^(d1) and R^(d) or R^(d1) and R^(d2) together with the carbon atoms    to which they are attached form 4, 5, or 6-atom heterocyclyl ring    wherein one or two ring atoms are replaced by oxygen or —N— where    the heterocyclyl ring is optionally substituted with one or two    alkyl;-   R^(d3) is aryl, heteroaryl, cycloalkyl or heterocyclyl optionally    substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,    cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino,    cycloalkylalkylcarbonylamino, alkyloxycarbonylamino, amino,    alkylamino, dialkylamino, or —NHCONRR′ where R is hydrogen or alkyl    and R′ is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl wherein    cycloalkyl and cycloalkylalkyl are optionally substituted with one,    two or three alkyl.

(i) Preferably,

-   R^(d1) is hydrogen, hydroxy, alkoxy, amino, alkylamino or    dialkylamino;-   R^(d) and R^(d2) are independently hydrogen, alkyl, halo, alkoxy,    alkylthio, or alkylsulfonyl; and-   R^(d3) is a group of formula:

optionally substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl,alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino,cycloalkylalkylcarbonylamino, alkyloxycarbonylamino, amino, alkylamino,dialkylamino, or —NHCONRR′ where R is hydrogen or alkyl and R′ ishydrogen, alkyl, cycloalkyl, or cycloalkylalkyl wherein cycloalkyl andcycloalkylalkyl are optionally substituted with one, two or three alkyl.

More preferably, R^(d3) is a group of formula:

optionally substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl,alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino,cycloalkylalkylcarbonylamino, alkyloxycarbonylamino, amino, alkylamino,dialkylamino, or —NHCONRR′ where R is hydrogen or alkyl and R′ ishydrogen, alkyl, cycloalkyl, or cycloalkylalkyl wherein cycloalkyl andcycloalkylalkyl are optionally substituted with one, two or three alkyl.

Even more preferably, R^(d3) is:

optionally substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl,alkoxy, cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino,cycloalkylalkylcarbonylamino, alkyloxycarbonylamino, amino, alkylamino,dialkylamino, or —NHCONRR′ where R is hydrogen or alkyl and R′ ishydrogen, alkyl, cycloalkyl, or cycloalkylalkyl wherein cycloalkyl andcycloalkylalkyl are optionally substituted with one, two or three alkyl.

Within the above preferred groups, a more preferred group of compoundsis that wherein:

-   R^(d1) is hydrogen, hydroxy, methoxy, ethoxy, n-propoxy,    iso-propoxy, methylamino, ethylamino, n-propylamino, isopropylamino,    dimethylamino, methylethylamino, methyl(n-propyl)amino and    methyl(isopropyl)amino; more preferably, hydrogen hydroxyl; methoxy    or dimethylamino, even more preferably methoxy. Alternatively, even    more preferably hydrogen;-   R^(d) and R^(d2) are independently, fluoro, chloro, methyl, ethynyl,    methoxy, ethoxy, thiomethyl or methylsulfonyl. More preferably,    R^(d) is hydrogen, ethynyl, fluoro, chloro, methyl, methoxy,    methylthio or methylsulfonyl and R^(d2) is hydrogen.

Most preferably, R^(d1) is methoxy, R^(d) is hydrogen or methyl, fluoro,chloro, or methoxy and R^(d2) is hydrogen.

(ii) Preferably, R² is a group of formula:

where:

-   Z^(a) and Z^(b) are independently —O— or —NH— where the H can be    replaced by R, preferably —O—;-   R is alkyl, preferably methyl;-   R^(d2) is hydrogen or methyl, preferably hydrogen; and-   R^(d3) is as defined for subgroup (i) immediately above.

(iii) Preferably, R² is a group of formula:

Z^(a) and Z^(b) are independently —O— or —NH— H can be replaced by R,preferably —O—;

-   R is alkyl, preferably methyl;-   R^(d) is hydrogen or methyl, preferably hydrogen; and-   R^(d3) is as defined for subgroup (i) above.

Within the above groups (i)-(iii), and more preferred groups containedtherein, a more preferred group of compounds is that wherein the R^(d3)rings are optionally substituted with methyl, ethyl, n-propyl, i-propyl,n-butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, 2,2,dimethylpropyl,1,2-dimethylpropyl, 1,2,2-trimethylpropyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl and cyclohexylmethyl each of said cycloalkyl andcycloalkylalkyl rings being optionally substituted with one to threesubstitutents independently selected from methyl or ethyl, preferablymethyl.

Within the above groups (i)-(iii), and more preferred groups containedtherein, a more preferred group of compounds is that wherein the R^(d3)rings are optionally substituted with amino, methylamino, ethylamino,propylamino, 1-methylethylamino, 1,1-dimethylethylamino,2-methylpropylamino, 1-methylpropylamino, 2,2-dimethylpropylamino,1,2-dimethylpropylamino, 1,1-dimethylpropylamino, cyclopropylamino,cyclobutylamino, cyclopentylamino, cyclohexylamino,cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino,cyclohexylmethylamino, methylcarbonylamino, ethylcarbonylamino,propylcarbonylamino, 1-methylethylcarbonylamino,1,1-dimethylethylcarbonylamino, 2-methylpropylcarbonylamino,1-methylpropylcarbonylamino, 2,2-dimethylpropylcarbonylamino,1,2-dimethylpropylcarbonylamino, 1,1-dimethylpropylcarbonylamino,cyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopentylcarbonylamino, cyclohexylcarbonylamino,cyclopropylmethylcarbonylamino, cyclobutylmethylcarbonylamino,cyclopentylmethylcarbonylamino, cyclohexyhnethylcarbonylamino,methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,1-methylethoxycarbonylamino, 1,1-dimethyl-ethoxycarbonylamino,2-methylpropoxycarbonylamino, 1-methylpropoxycarbonylamino,2,2-dimethylpropoxycarbonylamino, 1,2-dimethylpropoxylcarbonylamino, or1,1-dimethylpropoxy-carbonylamino.

(1) Within the above preferred group (C) and more preferred groupscontained therein, an even more preferred group of compounds is thatwherein:

-   X is —O—;-   R¹ is alkyl optionally substituted with alkoxy, alkylthio, or    alkylsulfonyl, alkenyl, alkynyl, or cycloalkylalkyl, preferably    alkyl or cycloalkylalkyl, preferably methyl, ethyl, n-propyl,    n-butyl, n-pentyl, prop-2-enyl, propyn-2-yl, 1-methylethyl,    1-methylpropyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl,    methoxymethyl, 2-methoxyethyl, methylthiomethyl,    methylsulfonylmethyl, or cyclobutylmethyl. More preferably    cyclobutylmethyl, ethyl, or n-propyl; and-   R³ is alkyl, aryl or cycloalkyl, preferably, 1-methylethyl,    1-methylpropyl, tert-butyl, cyclopropyl, phenyl, or cyclohexyl.    Preferably R³ is tert-butyl or cyclohexyl.

(a) Within this group C and C(1) and more preferred groups containedtherein a preferred group of compounds is that wherein:

-   E is —COCONHR⁶ where R⁶ is hydrogen, alkyl, cycloalkyl, aralkyl, or    heteroaralkyl wherein the aromatic ring is optionally substituted    with one or two halo, preferably, R⁶ is cyclopropyl, —CH(CH₃)R where    R is phenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,    3,4-dichlorophenyl, 3,4-difluorophenyl, or pyridin-4-yl. Preferably,    R⁶ is cyclopropyl.

(b) Within this group C and C(1) and more preferred groups containedtherein a preferred group of compounds is that wherein:

-   E is —COCOOR¹⁰ where R¹⁰ is as defined in the Summary of the    Invention. Preferably, R¹⁰ is —CH₂C≡CH, —CH₂CH═CH₂, n-propyl,    2,2-dimethylpropyl, carboxymethyl, methoxycarbonylmethyl,    tert-butoxycarbonylmethyl, —CH₂C(O)OCH₂C≡CH, —CH₂C(O)OCH₂CH═CH₂,    —CH₂C(O)O(CH₂)₂CH₃, —CH₂C(O)NH₂, —CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂,    —CH₂C(O)NHCH₂CH═CH₂, or 2-phenethyl.

(D) Yet another preferred group of compounds of Formula (I) is thatwherein R² is a group of formula (b):

where:

-   R^(d1) is hydrogen, hydroxy, alkoxy, amino, alkylamino,    dialkylamino, haloalkoxy or alkylsulfonyl;-   R^(d) and R^(d2) are independently hydrogen, alkyl, halo, alkoxy,    alkylthio, or alkylsulfonyl; or-   R^(d1) and R^(d) or R^(d1) and R^(d2) together with the carbon atoms    to which they are attached form 4, 5, or 6-atom heterocyclyl ring    wherein one or two ring atoms are replaced by oxygen or —N— where    the heterocyclyl ring is optionally substituted with one or two    alkyl;-   R^(d3) is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl.

(i) Preferably,

-   R^(d1) is hydrogen, hydroxy, alkoxy, amino, alkylamino or    dialkylamino;-   R^(d) and R^(d2) are independently hydrogen, alkyl, halo, alkoxy,    alkylthio, or alkylsulfonyl; and-   R^(d3) is a hydrogen, alkyl or cycloalkyl.

Within the above preferred groups, a more preferred group of compoundsis that wherein:

-   R^(d1) is hydrogen, hydroxy, methoxy, ethoxy, n-propoxy,    iso-propoxy, methylamino, ethylamino, n-propylamino, isopropylamino,    dimethylamino, methylethylamino, methyl(n-propyl)amino and    methyl(isopropyl)amino; more preferably, hydrogen hydroxyl; methoxy    or dimethylamino, even more preferably methoxy. Alternatively, even    more preferably hydrogen;-   R^(d) and R^(d2) are independently, fluoro, chloro, methyl, ethynyl,    methoxy, ethoxy, thiomethyl or methylsulfonyl. More preferably,    R^(d) is hydrogen, ethynyl, fluoro, chloro, methyl, methoxy,    methylthio or methylsulfonyl and R^(d2) is hydrogen.

Most preferably, R^(d1) is methoxy, R^(d) is hydrogen or methyl, fluoro,chloro, or methoxy and R^(d2) is hydrogen.

(1) Within the above preferred group (D) and more preferred groupscontained therein, an even more preferred group of compounds is thatwherein:

-   X is —O—;-   R¹ is alkyl optionally substituted with alkoxy, alkylthio, or    alkylsulfonyl, alkenyl, alkynyl, or cycloalkylalkyl, preferably    alkyl or cycloalkylalkyl, preferably methyl, ethyl, n-propyl,    n-butyl, n-pentyl, prop-2-enyl, propyn-2-yl, 1-methylethyl,    1-methylpropyl, 2-methylpropyl, 3-methylbutyl, cyclopropyl,    methoxymethyl, 2-methoxyethyl, methylthiomethyl,    methylsulfonylmethyl, or cyclobutylmethyl. More preferably    cyclobutylmethyl, ethyl, or n-propyl; and-   R³ is alkyl, aryl or cycloalkyl, preferably, 1-methylethyl,    1-methylpropyl, tert-butyl, cyclopropyl, phenyl, or cyclohexyl.    Preferably R³ is tert-butyl or cyclohexyl.

(a) Within this group D and D(1) and more preferred groups containedtherein a preferred group of compounds is that wherein:

-   E is —COCONHR⁶ where R⁶ is hydrogen, alkyl, cycloalkyl, aralkyl, or    heteroaralkyl wherein the aromatic ring is optionally substituted    with one or two halo, preferably, R⁶ is cyclopropyl, —CH(CH₃)R where    R is phenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,    3,4-dichlorophenyl, 3,4-difluorophenyl, or pyridin-4-yl. Preferably,    R⁶ is cyclopropyl.

(b) Within this group D and D(1) and more preferred groups containedtherein a preferred group of compounds is that wherein:

-   E is —COCOOR¹⁰ where R¹⁰ is as defined in the Summary of the    Invention. Preferably, R¹⁰ is —CH₂C≡CH, —CH₂CH═CH₂, n-propyl,    2,2-dimethylpropyl, carboxymethyl, methoxycarbonylmethyl,    tert-butoxycarbonylmethyl, —CH₂C(O)OCH₂C≡CH, —CH₂C(O)OCH₂CH═CH₂,    —CH₂C(O)O(CH₂)₂CH₃, —CH₂C(O)NH₂, —CH₂C(O)NHCH₃, —CH₂C(O)N(CH₃)₂,    —CH₂C(O)NHCH₂CH═CH₂, or 2-phenethyl.

It should be noted that reference to the preferred embodiments set forthabove includes all combinations of particular and preferred groupsunless stated otherwise.

General Synthetic Scheme

Compounds of this invention can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis,Mo.) or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition) and Larock's ComprehensiveOrganic Transformations (VCH Publishers Inc., 1989). These schemes aremerely illustrative of some methods by which the compounds of thisinvention can be synthesized, and various modifications to these schemescan be made and will be suggested to one skilled in the art havingreferred to this disclosure.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., more preferably from about 0° C. to about 125° C.and most preferably at about room (or ambient) temperature, e.g., about20° C.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1999.

Compounds of Formula (I) where Y is —OC(O)NH—, E is —COCONR⁵R⁶ and X,R¹, R², R³, and R⁴ are as defined in the Summary of the Invention can beprepared by proceeding as in the following Reaction Scheme 1 below.

Deprotection of the amino protecting group PG₁ such astert-butoxycarbonyl, benzyloxycarbonyl, and the like, in a pyrrolidinecompound of formula 1 where PG is a suitable carboxy protecting group,preferably alkyl, and X and R² are as defined in the Summary of theInvention provides a compound of formula 2. The reaction conditionsemployed for the amino protecting group depends on the nature of theprotecing group. For example, if PG₁ is tert-butoxycarbonyl, it isremoved by treatment of 1 with an acid such as hydrochloric acid in anorganic solvent such as dioxane, tetrahydrofuran, and the like. Othersuitable nitrogen protecting groups with reaction conditions for puttingthem on and removing them can be found in Greene, T. W.; and Wuts, P. G.M.; Protecting Groups in Organic Synthesis; John Wiley & Sons, Inc.1999. Compounds of formula 1 can be prepared by methods well known inthe art. Some such methods are described in US 2003191067, U.S. Pat.Nos. 6,608,027, 6,268,207, 6,404,397, 6,268,207, and WO 2005/028501, thedisclosures of which are incorporated herein by reference in theirentirety.

Treatment of compound 2 with an amino acid of formula 3 where R³ is asdefined in the Summary of the Invention under peptidic coupling reactionconditions provides a compound of formula 4 where Y is —O—C(O)NH— and R⁴is alkyl. The reaction is typically carried out in the presence of asuitable coupling agent e.g.,benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate(PyBOP®), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or1,3-dicyclohexyl-carbodiimide (DCC), optionally in the presence of1-hydroxy-benzotriazole (HOBT), and a base such asN,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and thelike. The reaction is typically carried out at 20 to 30° C., preferablyat about 25° C. Suitable reaction solvents are inert organic solventssuch as halogenated organic solvents (e.g., methylene chloride,chloroform, and the like), acetonitrile, N,N-dimethylformamide, etherealsolvents such as tetrahydrofuran, dioxane, and the like or mixturesthereof. Amino acids of formula 3 are either commercially available orthey can be prepared by methods well known in the art.

Hydrolysis of the ester group in compound 4 (PG=alkyl) under aqueousbasic hydrolysis reaction conditions provides a compound of formula 5.The reaction is typically carried out with cesium carbonate, lithiumhydroxide, sodium hydroxide, and the like in an aqueous alcohol such asmethanol, ethanol, and the like.

Treatment of compound 5 with an α-hydroxyaminocarboxamide of formula 6under peptidic coupling reaction conditions as described above providesa compound of formula 7. Compounds of formula 6 can be prepared bymethods well known in the art some of which are described in details inworking examples, References A and B below. Compound 6 can also beprepared from compound 17 (whose synthesis is described in Scheme 3below). Briefly, after suitable protection of the amino group (forexample as the t-Boc carbamate), the ester group of compound 17 isremoved under basic hydrolysis reaction conditions to form thecorresponding α-hydroxy acid. Treatment of the acid with an amine offormula NHR⁵R⁶ under coupling reaction conditions followed by acidcatalyzed hydrolysis of the amine protecting group provides a compoundof formula 6.

Alternatively, the above coupling step can be carried out by firstconverting 5 into an active acid derivative such as acid halide,succinimide ester, and the like, and then reacting it with anα-hydroxyketoamide of formula 6. The conditions utilized in thisreaction depend on the nature of the active acid derivative. Forexample, if it is an acid chloride derivative of 5, the reaction iscarried out in the presence of a suitable base (e.g. triethylamine,diisopropylethylamine, pyridine, and the like). Suitable reactionsolvents are polar organic solvents such as acetonitrile,N,N-dimethylformamide, dichloromethane, or any suitable mixturesthereof. Oxidation of the hydroxy group in compound 8 with a suitableoxidizing agent such as Dess Martin Periodinane provides a compound ofFormula (I).

Compounds of Formula (I) where Y is —NHC(O)NH—, E is —COCONR⁵R⁶ and X,R¹, R², R³, and R⁴ are as defined in the Summary of the Invention can beprepared by proceeding as in the following Reaction Scheme 2 below.

Removal of the Boc group in compound 4 under acid hydrolysis reactionconditions provides an amino compound of formula 9 which upon reactionwith an alkyl isocyanate provides a ureido compound of formula 10. Thereaction is carried out in the presence of an organic base suchtriethylamine, pyridine, and the like and in a suitable organic solventsuch as dichloromethane, and the like. The ureido compounds can also beprepared by other methods well known in the art such as reaction ofcompound 9 with carbamoyl halides. Compound 10 is then converted to acompound of Formula (I) by proceeding as described in Scheme 1 above.Similarly compounds of Formula (I) where R⁴ is other than alkyl can beprepared by substituting alkyl isocyanate with aryl-, heteroaryl-, oraralkyl-isocyanates or carbamyl halides.

Similarly, compound of Formula (I) where Y is —CONH— or —SO₂NH— can beprepared by reacting compound 9 with an acylating agent or formula R⁴COLrespectively under conditions well known in the art.

Alternatively, compounds of Formula (I) can be prepared from compound 4by deprotecting the acid protecting group to give the correspondingacid. The acid is reacted with the α-hydroxyaminocarboxamide 6 followedby removal of the Boc [alkylOC(O)—] group in the resulting product togive the free amino compound. Reaction of the amino compound with alkylisocyanates or carbamyl halide gives compound 12 which is then convertedto compound of Formula (I) upon oxidation of the hydroxyl group asdescribed above.

Compounds of Formula (I) where E is —COCOOR¹⁰ and X, Y, R¹, R², R³, R⁴,and R¹⁰ are as defined in the Summary of the Invention can be preparedby proceeding as in the following Reaction Scheme 3 below.

Treatment of a N-Boc-protected amino acid compound of formula 13 withN,O-dimethylamine under conditions well known in the art provides theWeinreb amide compound of formula 14. Compounds of formula 13 can beprepared from commercially available amino acids withtert-butoxycarbonyl anhydride under conditions well known in the art.Other suitable amino protecting groups can be utilized as well.Treatment of compound 14 with a suitable reducing agent such as lithiumaluminium hydride in a suitable organic solvent such as tetrahydrofuran,and the like provides the corresponding aldehyde of formula 15.Treatment of compound 15 with acetone cyanohydrin provides compound 16which is then reacted with acid halide in a hydroxyl compound of formulaR¹⁰OH where R¹⁰ is as defined in the Summary of the Invention to givethe alpha hydroxyl ester compound of formula 17.

Treatment of compound 17 with a compound of formula 5, under peptidecoupling conditions as described earlier, followed by oxidation of thehydroxyl group in the resulting product provides a compound of Formula(I) where Y is —OC(O)NH— and R⁴ is alkyl. Compound of Formula (I) whereY is —OC(O)NH— and R⁴ is alkyl can be converted to other compounds ofFormula (I) where Y and R⁴ are as defined in the Summary of theInvention as described above.

Compounds of Formula (I) where E is —CONR¹¹R¹² and X, Y, R¹, R², R³, R⁴,R¹¹, and R¹² are as defined in the Summary of the Invention can beprepared by proceeding as in the following Reaction Scheme 4 below.

Treatment of compound 13 with an amine of formula NHR¹¹R¹² undercoupling reaction conditions described above provides a compound offormula 18. Removal of the Boc group under acidic hydrolysis reactionconditions provides compound 19 which is then converted to compound ofFormula (I) as described above.

Compounds of Formula (I) where E is —COR⁹ and X, Y, R¹, R², R³, R⁴, andR⁹ are as defined in the Summary of the Invention can be prepared byproceeding as in the following Reaction Scheme 5 below.

Treatment of a compound of formula 15 with an organolithium or Grignardreagent of formula R⁹Li or R⁹MgX respectively where R⁹ is as defined inthe Summary of the Invention provides a compound of formula 20. Thereaction is typically carried out at low reaction temperatures such as−78° C. and in an organic solvent such as tetrahydrofuran, and the like.Removal of the Boc group provides compound 21 with upon reaction withcompound 5 under coupling reaction conditions described above provides acompound of formula 22. Oxidation of the hydroxyl group then provides acompound of Formula (I) where Y is —OC(O)NH— and R⁴ is alkyl. Compoundsof Formula (I) where Y and R⁴ are other groups as defined in the Summaryof the Invention can be prepared as described above.

Compounds of Formula (I) where E is —CHO and X, Y, R¹, R², R³, R⁴, andR⁸ are as defined in the Summary of the Invention can be prepared byproceeding as in the following Reaction Scheme 6 below.

Removal of the amino protecting group in compound 23 under acidichydrolysis reaction conditions, followed by coupling of the resultingamino compound with a compound of formula 5 provides a compound offormula 24. Compound 24 is then converted to a compound of Formula (I)where E is —CHO by proceeding as shown in method A or B above.

In method A, hydrolysis of the ester group under basic hydrolysisreaction conditions provides a compound of formula 25 which is convertedto a Weinreb amide of formula 26. Reduction of the amido group in 26with a suitable reducing agent such as lithium alumimun hydride thenprovides a compound of Formula (I) where E is —CHO and Y is —OC(O)NH—.

Alternatively, the ester group in compound 24 can be reduced with asuitable reducing agent such as lithium alumimun hydride to provide thecorresponding alcohol of formula 27 which upon treatment with anoxidizing agent provides a compound of Formula (I) where E is —CHO and Yis —OC(O)NH—. Compounds of Formula (I) where Y is other groups can beprepared as described above.

A compound of Formula (I) can be converted to other compounds of Formula(I). For example:

A compound of Formula (I) containing a hydroxy group may be prepared byde-alkylationlbenzylation of an alkoxy/benzyloxy substituent; thosecontaining an acid group, by hydrolysis of an ester group; and thosecontaining a cyano, by displacement of a bromine atom on thecorresponding compounds of Formula (I). A compound of Formula (I)containing a cyano group can be converted to a corresponding carboxycontaining compound by hydrolysis of the cyano group. The carboxy group,in turn, can be converted to an ester group.

A compound of Formula (I) can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of Formula (I) can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase. Inorganic and organic acids and bases suitable for the preparationof the pharmaceutically acceptable salts of compounds of Formula (I) areset forth in the definitions section of this Application. Alternatively,the salt forms of the compounds of Formula (I) can be prepared usingsalts of the starting materials or intermediates.

The free acid or free base forms of the compounds of Formula (I) can beprepared from the corresponding base addition salt or acid addition saltform. For example, a compound of Formula (I) in an acid addition saltform can be converted to the corresponding free base by treating with asuitable base (e.g., ammonium hydroxide solution, sodium hydroxide, andthe like). A compound of Formula (I) in a base addition salt form can beconverted to the corresponding free acid by treating with a suitableacid (e.g., hydrochloric acid, etc).

The N-oxides of compounds of Formula (I) can be prepared by methodsknown to those of ordinary skill in the art. For example, N-oxides canbe prepared by treating an unoxidized form of the compound of Formula(I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleicacid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, orthe like) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0° C.Alternatively, the N-oxides of the compounds of Formula (I) can beprepared from the N-oxide of an appropriate starting material.

Compounds of Formula (I) in unoxidized form can be prepared fromN-oxides of compounds of Formula (I) by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of Formula (I) can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al.(1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of Formula (I) with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of Formula (I) can be made bymeans known to those of ordinary skill in the art. A detaileddescription of the techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, Protecting Groupsin Organic Synthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds of the present invention may be conveniently prepared orformed during the process of the invention, as solvates (e.g. hydrates).Hydrates of compounds of the present invention may be convenientlyprepared by recrystallisation from an aqueous/organic solvent mixture,using organic solvents such as dioxin, tetrahydrofuran or methanol.

Compounds of Formula (I) can be prepared as diastereomers that havedistinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.) and can be readily separated by takingadvantage of these dissimilarities. The diastereomers can be separatedby chromatography or, preferably, by separation/resolution techniquesbased upon differences in solubility. The optically pure isomer is thenrecovered by any practical means that would not result in racemizationof its chiral centers. A more detailed description of the techniquesapplicable to the resolution of stereoisomers of compounds from theirracemic mixture can be found in Jean Jacques Andre Collet, Samuel H.Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc.(1981).

Pharmacology and Utility

The compounds of the present invention are inhibitors of hepatitis Cvirus (HCV) replication and are therefore useful in treating hepatitis Cinfections. The inhibitory activities of the compounds of Formula (I)can be determined by methods known to those of ordinary skill in theart. A suitable in vitro assay for measuring the ability of compounds ofthis invention to inhibit HCV replication is set forth in BiologicalExample 1 infra.

Administration and Pharmaceutical Compositions

In general, compounds of Formula (I) will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Forexample, therapeutically effective amounts of a compound of Formula (I)may range from about 10 micrograms per kilogram body weight (μg/kg) perday to about 100 milligram per kilogram body weight (mg/kg) per day,typically from about 100 μg/kg/day to about 10 mg/kg/day. Therefore, atherapeutically effective amount for an 80 kg human patient may rangefrom about 1 mg/day to about 8 g/day, typically from about 1 mg/day toabout 800 mg/day. In general, one of ordinary skill in the art, actingin reliance upon personal knowledge and the disclosure of thisApplication, will be able to ascertain a therapeutically effectiveamount of a compound of Formula (I) for treating a given disease.

The compounds of Formula (I) can be administered as pharmaceuticalcompositions by one of the following routes: oral, systemic (e.g.,transdermal, intranasal or by suppository) or parenteral (e.g.,intramuscular, intravenous or subcutaneous). Compositions can take theform of tablets, pills, capsules, semisolids, powders, sustained releaseformulations, solutions, suspensions, elixirs, aerosols, or any otherappropriate composition and are comprised of, in general, a compound ofFormula (I) in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the activeingredient. Such excipient may be any solid, liquid, semisolid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk, and the like. Liquid and semisolid excipientsmay be selected from water, ethanol, glycerol, propylene glycol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesameoil, and the like). Preferred liquid carriers, particularly forinjectable solutions, include water, saline, aqueous dextrose andglycols.

The amount of a compound of Formula (I) in the composition may varywidely depending upon the type of formulation, size of a unit dosage,kind of excipients and other factors known to those of skill in the artof pharmaceutical sciences. In general, a composition of a compound ofFormula (I) for treating a given disease will comprise from 0.01% w to90% w, preferably 5% w to 50% w, of active ingredient with the remainderbeing the excipient or excipients. Preferably the pharmaceuticalcomposition is administered in a single unit dosage form for continuoustreatment or in a single unit dosage form ad libitum when relief ofsymptoms is specifically required. Representative pharmaceuticalformulations containing a compound of Formula (I) are described below.

In some embodiments, the compounds of Formula (I) can be administered toa patient in need of treatement with a second antiviral agent. Examplesof suitable antiviral agents are interferons, such as Intron A, RoferonA and pegylated interferons such as PEG-intron, Pegasys; Ribavirin,Viramidine, Levovirin; HCV polymerase inhibitors such as Valopicitabine,R 1626 (Roche), HCV-796 (Viropharma/Wyeth); and toll receptor agonistssuch as ANA-975 (Anadys). The compounds of Formula (I) can beadministered in a combination with the above agents or separately.Additionally, the compounds of Formula (I) can be administered eitherprior to, or following, the administration of a second antiviral agent,according to a physician prescribed regimen.

EXAMPLES

The present invention is further exemplified, but not limited by, thefollowing examples that illustrate the preparation of compounds ofFormula (I) according to the invention.

Reference A Synthesis of[1S-(cyclopropylcarbamoylhydroxymethyl)butyl]carbamic acid tert-butylester

To the mixture of Boc-NVa-OH (25 g, 0.115 mol), N,O-dimethylhydroxyaminehydrochloride (12.34 g, 0.127 mol), EDC (33.07 g, 0.173 mol), HOBt (22.9g, 0.15 mol) in dichloromethane (300 mL), was slowly added NMM (34.9 g,0.35 mol) under stirring in 30 min. The reaction was left at roomtemperature for 2 h, then diluted with 2000 mL EtOAc, washed withNaHCO₃, H₂O, and brine, and dried over MgSO₄. The solvent was removed onrotovap to give [1S-(methoxymethylcarbarnoyl)butyl]carbamic acidtert-butyl ester (20 g) as colorless oil.

Step 2

To the solution of [1S-(methoxymethylcarbamoyl)butyl]carbamic acidtert-butyl ester (7.2 g, 27.7 mmol) in anhydrous THF (100 mL) underargon at −78° C., was slowly added LAH (1M in THF, 27.7 mL). After 2 h,the reaction mixture was quenched by slowly adding 1N HCl (20 mL) andthen allowed to warm up to room temperature. The reaction mixture wasdiluted with EtOAc (600 mL), washed with 1N HCl, H₂O, and brine anddried over MgSO₄. Removal of the solvents gave (1S-formylbutyl)carbamicacid tert-butyl ester (4.8 g) as an oil.

Step 3

To a solution of cyclopropylisonitrile (1.91 g, 28.5 mmol),(1S-formylbutyl)carbamic acid tert-butyl ester (3.8 g, 19 mmol) inmethylene chloride (100 mL) was added acetic acid (2.28 g, 38 mmol) at0° C. After the addition was complete the reaction mixture was allowedto warm to 25° C. and stirred for 6 h. The reaction mixture was dilutedwith EtOAc (200 mL), then washed with satured solution of NaHCO₃ andbrine (30 mL) and dried over MgSO₄. The solvent was removed and thecrude product was crystallized from 50 mL of ethyl acetate andhexane(v/v=1/1) to give acetic acid2-tert-butoxycarbonylamino-1-cyclopropylcarbamoylpentyl ester (4.8 g) asa white solid.

Step 4

Into the solution of acetic acid2-tert-butoxycarbonylamino-1-cyclopropylcarbamoyl-pentyl ester (4.8 g,14.6 mmol) in methanol (50 mL) was added NaOH aqueous solution (1N, 22mL) at room temperature. After 2 h, methanol was removed and theconcentrate was extracted with ethyl acetate (300 mL). The ethyl acetatelayer was washed with brine and dried over MgSO₄. After removal of thesolvent, the crude product was crystallized from 100 mL of ethyl acetateand hexane(v/v=3/1) to give the title compound (3.5 g) as a white solid.

Reference B Synthesis of(1S-cyclobutylmethyl-2-cyclopropylcarbamoyl-2-hydroxyethyl)-carbamicacid tert-butyl ester

Step 1

To the mixture of Boc-L-cyclobutylalanine.DIPA (10.33 g, 30 mmol),N,O-dimethylhydroxyamine hydrochloride (3.22 g, 33 mmol), EDC (8.63 g,45 mmol), HOBt (5.52 g, 36 mmol) in dichloromethane (200 mL), was slowlyadded NMM (9.11 g, 90 mmol) with stirring over 30 min. After 2 h, thereaction mixture was diluted with EtOAc (1000 mL), washed with NaHCO₃,H₂O, and brine and dried over MgSO₄. Removal of the solvent gave[2-cyclobutyl-1S-(methoxymethylcarbamoyl)ethyl]-carbamic acid tert-butylester (7.1 g) as a colorless oil.

Step 2

To the solution of[2-cyclobutyl-1S-(methoxymethylcarbamoyl)ethyl]-carbamic acid tert-butylester (4.3 g, 15 mmol) in anhydrous THF (100 mL) under argon at −78° C.,was slowly added LAH (1M in THF, 15 mL, 15 mmol). After 2 h, thereaction mixture was quenched by slowly adding 1N HCl (15 mL) and thereaction mixture was warmed up to room temperature after the additionwas complete. The reaction mixture was diluted with EtOAc (500 mL),washed with 1N HCl, H₂O, and brine and dried over MgSO₄. Removal of thesolvents gave (2-cyclobutyl-1S-formylethyl)carbamic acid tert-butylester (2.95 g) as an oil.

Step 3

To a solution of cyclopropylisonitrile (1.21 g, 18 mmol),(2-cyclobutyl-1S-formylethyl)carbamic acid tert-butyl ester (2.95 g, 13mmol) in methylene chloride(20 mL), was added acetic acid (1.56 g, 26mmol) at 0° C. After the addition was complete, the reaction mixture wasallowed to warm to 25° C. and stirred for another 4 h. The reactionmixture was diluted with 200 mL EtOAc and washed with saturated solutionof NaHCO₃ and brine and dried over MgSO₄. The solvent was removed andthe crude product was crystallized from 50 mL of ethyl acetate andhexane (v/v=1/1) to give acetic acid2S-tert-butoxycarbonylamino-3-cyclobutyl-1-cyclopropylcarbamoylpropylester (3.8 g) as a white solid.

Step 4

To a solution of acetic acid2S-tert-butoxycarbonylamino-3-cyclobutyl-1-cyclopropylcarbamoylpropylester (3.8 g, 10.7 mmol) in methanol (50 mL) was added NaOH aqueoussolution (1N, 15 mL) at room temperature. After 2 h, methanol wasremoved and the concentrate was extracted with ethyl acetate. The ethylacetate was washed with brine and dried over MgSO₄. The solvent wasremoved and the residue was crystallized from 100 mL of ethyl acetateand hexane(v/v=3/1) to give the title compound (2.9 g) as a white solid.

Example 1 Synthesis of1-[2S-(3-tert-butylureido)-3,3-dimethylbutyryl]-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclopropylaminooxalylbutyl)amide (7)

Step 1

To a solution of commercially availableN-tert-Boc-cis-4S-hydroxy-L-proline methyl ester (370 mg, 1.51 mmol) and7-methoxy-2-pyrazol-1-yl-quinolin-4-ol (PCT application publication No.WO 2000059929) (400 mg, 1.66 mmol) in dry THF (15 mL) at 0° C. was addedtriphenylphosphine (594 mg, 2.27 mmol), followed by a slow addition ofDIAD (0.36 mL, 1.81 mmol) under N₂. The reaction mixture was slowlyallowed to warm to room temperature and stirred for 18 h. The crudereaction mixture was then concentrated and purified by flashchromatography to give the4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester-2S-methyl ester (1) in 69% yield.

Step 2

To a solution of4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester-2S-methyl ester (200 mg, 0.43 mmol) indichloromethane (1 mL) was added 4.0 M HCl in dioxane (3.0 mL). After 1h, the reaction mixture was concentrated and dried to give4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid methyl ester hydrochloride (2) as a white solid.

Step 3

To a solution of4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine 2S-carboxylicacid methyl ester hydrochloride (67 mg, 0.165 mmol) indichloromethane/DMF (2.0 mL, 1:1) was added Boc-L-tert-Leu-OH (38.1 mg,0.165 mmol), HATU (69 mg, 0.182 mmol) and DIPEA (0.1 mL, 0.5 mmol) andthe mixture was stirred at rt. After 16 h, the reaction mixture wasdiluted with ethyl acetate and washed with 1N HCl, saturated NaHCO₃, andbrine. The ethyl acetate layer was dried (MgSO₄), filtered andevaporated to dryness to give1-(2S-tert-butoxycarbonylamino-3,3-dimethylbutyryl)-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid methyl ester (3) in quantitative yield.

Step 4

To a solution of crude1-(2S-tert-butoxycarbonylamino-3,3-dimethylbutyryl)-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid methyl ester in dichloromethane (1 mL) was added 4.0 M HCl indioxane (3.0 mL). After 1 h, the reaction mixture was concentrated anddried to give1-(2S-amino-3,3-dimethylbutyryl)-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid methyl ester HCl salt as a white solid which was used in the nextstep without further purification.

Step 5

To a solution of 1-(2S-amino-3,3-dimethylbutyryl)-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid methyl ester HCl salt (0.165 mmol) in dichloromethane (3.0 mL) wasadded triethylamine (0.06 mL, 0.413 mmol) and tert-butylisocyanate (0.02mL, 0.165 mmol) and the reaction mixture was stirred at rt. After 16 h,the reaction mixture was diluted with dichloromethane and washed with 1NHCl, saturated NaHCO₃, and brine. The dichloromethane layer was thenevaporated to dryness to give1-[2S-(3-tert-butyl-ureido)-3,3-dimethyl-butyryl]-4R-(7-methoxy-2-pyrazol-1-ylquinolin-4-yloxy)-pyrrolidine-2S-carboxylic acid methyl ester (4).

Step 6

1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(7-methoxy-2-pyrazol-1-ylquinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid methyl ester was treated with methanol (6.0 mL), THF (3.0 mL) and1N NaOH (6. mL). After 1 h at rt, the reaction mixture was concentrated,acidified with 1N HCl and extracted with ethyl acetate. The combinedethyl acetate layers were then washed with brine and dried (MgSO₄). Theethyl acetate layer was then filtered and evaporated to dryness to give1-[2S-(3-tert-butyl-ureido)-3,3-dimethyl-butyryl]-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid (5).

Step 7

[1S-(Cyclopropylcarbamoylhydroxymethyl)butyl]carbamic acid tert-butylester (48 mg, 0.165 mmol) was dissolved in dichloromethane (3.0 mL) andTFA (3.0 mL) was added. After stirring for 1 h at rt, the reactionmixture was evaporated to dryness to give 3S-amino-2-hydroxyhexanoicacid cyclopropylamide TFA salt as a white solid. A solution of1-[2S-(3-tert-butylureido)-3,3-dimethyl-butyryl]-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid in dichloromethane/DMF (1:1. 6.0 mL) was added to3S-amino-2-hydroxyhexanoic acid cyclopropylamide TFA salt followed byHATU (75 mg, 0.198 mmol) and DIPEA (0.1 mL, 0.7 mmol). After 24 h at rt,the reaction mixture was diluted with ethyl acetate and washed with 1NHCl, NaHCO₃, and brine. The ethyl acetate layer was dried (MgSO₄),filtered and evaporated to dryness. The crude product was then dissolvedin dry dichloromethane (10.0 mL) and Dess-Martin periodinane (112 mg,0.264 mmol) was added. After stirring at rt for 2 h, the reactionmixture was quenched with 0.26M Na₂S₂O₃ in saturated NaHCO₃ andextracted with ethyl acetate. The combined ethyl acetate layers werethen washed with saturated NaHCO₃ and brine. Purification by preparativeHPLC gave the title compound (7) in >99% purity by HPLC.

1H NMR: (DMSO-d₆) δ 8.76-8.70 (m, 2H); 8.22 (d, J=6.8 Hz, 1H); 8.11 (d,J=9.6 Hz, 1H); 7.87 (d, J=1.2 Hz, 1H); 7.45 (s, 1H); 7.27 (d, J=2.4 Hz,1H); 7.00-6.97 (dd, J=2.8 and 9.6 Hz, 1H); 6.64-6.62 (m, 1H); 5. 92(brs, 1H); 5.49 (brs, 1H); 5.00-4.96 (m, 1 H); 4.55-4.49 (m, 2H); 4.18(d, J=5.6 Hz, 1H); 3.90 (s, 3H); 3.91-3.82 (m, 1H); 3.54 (brs, 1H);2.75-2.72 (m, 1H); 2.54-2.51 (m, 1H); 2.17-2.14 (m, 1H); 1.69-1.66 (m,1H); 1.40-1.34 (m, 3H); 1.13 (m, 9H); 0.93 (m, 9H); 0.90-0.82 (m, 3H);0.65-0.53 (m, 4H). MS (M⁺+1) 733.

Example 2 Synthesis of1-[2S-(3-tert-butylureido)-3,3-dimethylbutyryl]-4R-(7-methoxy-2-pyrazol-1-ylquinolin-4-yloxy)-pyrrolidine-2-carboxylic acid(1S-cyclobutylmethyl-2-cyclopropylcarbamoyl-2-oxoethyl)amide (9)

Step 1

(1S-Cyclobutylmethyl-2-cyclopropylcarbamoyl-2-hydroxy-ethyl)-carbamicacid tert-butyl ester (51 mg, 0.165 mmol) was dissolved indichioromethane (3.0 mL) and TFA (3.0 mL) was added. After stirring for1 h at rt, the reaction mixture was evaporated to dryness to give3S-amino-4-cyclobutyl-N-cyclopropyl-2-hydroxy-butyramide TFA salt as awhite solid. A solution of 1-[2S-(3-tert-butylureido)-3,3-dimethyl-butyryl]-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid in dichloromethane/DMF (1:1. 6.0 mL) to added to3S-amino-4-cyclobutyl-N-cyclopropyl-2-hydroxy-butyramide TFA saltfollowed by HATU (75 mg, 0.198 mmol) and DIPEA (0.1 mL, 0.7 mmol). After24 h at rt, the reaction mixture was diluted with ethyl acetate andwashed with 1N HCl, saturated NaHCO₃, and brine. The ethyl acetate layerwas dried (MgSO₄), filtered and evaporated to dryness. The crude productwas then dissolved in dry dichloromethane (10.0 mL) and Dess-Martinperiodinane (112 mg, 0.264 mmol) was added. After stirring at rt for 2h, the reaction mixture was quenched with 0.26M Na₂S₂O₃ in saturatedNaHCO₃ and extracted with ethyl acetate. The combined ethyl acetatelayers were then washed with saturated NaHCO₃ and brine. Purification bypreparative HPLC gave the title compound (9) in >99% purity by HPLC.

¹H NMR: (DMSO-d₆) δ 8.76-8.69 (m, 2H); 8.19 (d, J=8.0 Hz, 1H); 8.10 (d,J=8.0 Hz, 1H); 7.87-7.86 (m, 1H); 7.45 (s, 1H); 7.27 (d, J=2.8 Hz, 1H);7.00-6.97 (dd, J=2.8 and 9.6 Hz, 1H); 6.64-6.62 (m, 1H); 5. 93 (brs,1H); 5.48 (brs, 1H); 5.00-4.96 (m, 1H); 4.53-4.49 (m, 2H); 4.18 (d,J=9.2 Hz, 1H); 3.90 (s, 3H); 3.91-3.82 (m, 1H); 3.42 (brs, 2 H);2.75-2.72 (m, 1H); 2.54-2.51 (m, 1H); 2.17-2.14 (m, 1H); 1.96-1.89 (m,2H); 1.78-1.50 (m, 6H); 1.13 (m, 9H); 0.94 (m, 9H); 0.65-0.53 (m, 4H).MS (M++1) 759.

Example 3 Synthesis of1-[2S-(3-tert-butylureido)-3,3-dimethylbutyryl]-4R-(5-chloropyridin-2-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclobutylmethyl-2-cyclopropylcarbamoyl-2-oxoethyl)-amide (15)

Preparation of 10, HCL Salt

To commercially available t-Boc-(2S,4R)-hydroxyproline (1 mmol) in DMSOwas added potassium tert-butoxide (3 mmol) in small portions over 15 minat 23° C. The mixture was stirred at 23° C for 30 min, then cooled to 0°C. before adding 2,5-dichloropyridine (1.1 mmol) in small portions over10 min. The reaction mixture was stirred at 23° C. for 16 h. Theresulting suspension was poured into 5% aqueous citric acid andextracted with EtOAc. The combined EtOAc layers were washed with brineand dried (MgSO4). The organic portions were filtered and concentratedto give a white solid. The solid material was dissolved in 4.0 M HCl indioxane (10 mL). After 1 h, the reaction mixture was concentrated anddried to give 4R-(5-Chloropyridin-2-yloxy)-pyrrolidine-2S-carboxylicacid methyl ester HCl salt.

Step 1

To 4R-(5-Chloropyridin-2-yloxy)-pyrrolidine-2S-carboxylic acid methylester HCl salt (242 mg, 0.829 mmol) in dichloromethane/DMF (10 mL, 1:1)was added Boc-L-tert-Leu-OH (192 mg, 0.829 mmol), HATU (347 mg, 0.912mmol) and DIPEA (0.37 mL, 2.07 mmol) and the reaction mixture wasstirred at rt. After 16 h, the reaction mixture was diluted with ethylacetate and washed with saturated NaHCO₃, and brine. The ethyl acetatelayer was dried (MgSO₄), filtered and evaporated to dryness to give1-(2S-tert-butoxycarbonylamino-3,3-dimethylbutyryl)-4-(5-chloro-pyridin-2-yloxy)-pyrrolidine-2S -carboxylic acid methyl ester (11) in quantitative yield.

Step 2

1-(2S-tert-Butoxycarbonylamino-3,3-dimethylbutyryl)-4R-(5-chloropyridin-2-yloxy)-pyrrolidine-2S-carboxylicacid methyl ester was treated with methanol (5.0 mL), THF (3.0 mL) and1N NaOH (5.0 mL). After 2 h at rt, the reaction mixture wasconcentrated, acidified with 1N HCl and extracted with ethyl acetate.The combined ethyl acetate layers were then washed with brine and dried(MgSO₄). The ethyl acetate layer was then filtered and evaporated todryness to give1-(2S-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4R-(5-chloro-pyridin-2-yloxy)-pyrrolidine-2S-carboxylicacid (12).

Step 3

To (1S-Cyclobutylmethyl-2-cyclopropylcarbamoyl-2-hydroxy-ethyl)-carbamicacid tert-butyl ester (214 mg, 0.83 mmol) was added 4.0 M HCl in dioxane(11.0 mL). After 1 h, the reaction mixture was concentrated and dried togive 3S-amino-4-cyclobutyl-N-cyclopropyl-2-hydroxy-butyramide HCl saltas a white solid. To3S-amino-4-cyclobutyl-N-cyclopropyl-2-hydroxy-butyramide was added1-(2S-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4R-(5-chloro-pyridin-2-yloxy)-pyrrolidine-2S-carboxylicacid in dichloromethane/DMF (1:1. 10.0 mL), EDC (238 mg, 1.24 mmol),HOBt (190 mg, 1.24 mmol) and NMM (0.6 mL, 3.32 mmol). After 16 h at rt,the reaction mixture was diluted with ethyl acetate and washed withsaturated NaHCO₃, brine, and dried (MgSO₄). The ethyl acetate layer wasthen filtered, concentrated and purified by flash chromatography to give{1-[4R-(5-chloropyridin-2-yloxy)-2S-(1S-cyclobutylmethyl-2-cyclopropylcarbaamoyl-2-hydroxyethyl-carbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl}-carbamicacid tert-butyl ester (13) in 58% yield.

Step 4

To{1-[4R-(5-chloropyridin-2-yloxy)-2S-(1S-cyclobutylmethyl-2-cyclopropylcarbamoyl-2-hydroxyethyl-carbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl}-carbamicacid tert-butyl ester (313 mg, 0.482 mmol) in dichloromethane (2 mL) wasadded 4.0 M HCl in dioxane (3.0 mL). After 1 h, the reaction mixture wasconcentrated and dried to give1-(2S-amino-3,3-dimethylbutyryl)-4R-(5-chloropyridin-2-yloxy)-pyrrolidine-2-carboxylicacid (1-cyclobutyl-methyl-2-cyclopropylcarbamoyl-2-hydroxyethyl)-amideHCl salt as a white solid.

Step 5

To a solution of1-(2S-amino-3,3-dimethylbutyryl)-4R-(5-chloropyridin-2-yloxy)-pyrrolidine-2-carboxylicacid (1-cyclobutyl-methyl-2-cyclopropylcarbamoyl-2-hydroxyethyl)-amideHCl salt (45 mg, 0.077 mmol) in dichloromethane (3.0 mL) was addedtriethylamine (0.02 mL, 0.154 mmol). After 5 min at rt,tert-butylisocyanate (0.01 mL, 0.077 mmol) was added and the reactionmixture was stirred at rt. After 16 h, the reaction mixture was dilutedwith dichloromethane and washed with 1N HCl, saturated NaHCO₃, andbrine. The dichloromethane layer was then evaporated to dryness to give1-[2S-(3-tert-butyl-ureido)-3,3-dimethyl-butyryl]-4R-(5-chloropyridin-2-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclobutylmethyl-2-cyclopropylcarbamoyl-2-hydroxyethyl)amide(14).

Step 6

1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(5-chloropyridin-2-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclobutylmethyl-2-cyclopropylcarbamoyl-2-hydroxyethyl)amidewas dissolved in dry dichloromethane (4.0 mL) and Dess-Martinperiodinane (44 mg, 0.103 mmol) was added. After stirring at rt for 2 hreaction mixture was quenched with 0.26M Na₂S₂O₃ in saturated NaHCO₃ andextracted with ethyl acetate. The combined ethyl acetate layers werethen washed with saturated NaHCO₃ and brine. Purification by preparativeHPLC gave the title compound (15) in >90% purity by HPLC.

¹H NMR: (DMSO) 8.91-8.73 (m, 1H); 8.30-8.24 (m, 2H); 7.92-7.7.80 (m,1H); 6.94-6.84 (m, 1H); 5.97 (brs, 1H); 5.50 (s, 1H); 5.00-4.95 (m, 1H);4.54-4.52 (m, 1H); 4.17-3.88 (m, 3H); 2.75-2.72 (m, 1H); 2.54-2.51 (m,1H); 2.40-2.32 (m, 1H); 2.17-1.60 (m, 10H); 1.13 (m, 9H); 0.91 (m, 9H);0.67-0.58 (m, 4H). MS (M⁺+1) 648.

Example 4 Synthesis of{1S-[2S-(1S-cyclopropylaminooxalylbutylcarbamoyl)-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-1-carbonyl]-2,2-dimethylpropyl}-carbamicacid tert-butyl ester (16)

Proceeding as described in Example 1 above, provided{1S-[2R-(1S-cyclopropylamino-oxalylbutylcarbamoyl)-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-1-carbonyl]-2,2-dimethylpropyl}carbamicacid tert-butyl ester. MS: 734 (M+1)MS: 734 (M+1). cl Example 5

Synthesis of{1S-[2S-(1S-cyclopropylaminooxalylbutylcarbamoyl)-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-1-carbonyl]-2,2-dimethylpropyl}-carbamicacid tert-butyl ester (17)

Proceeding as described in Example 4 above, but substituting7-methoxy-2-pyrazol-1-yl-quinolin-4-ol with7-methoxy-2-phenyl-quinolin-4-ol provided the title compound. MS: 744(M+1)

Example 6 Synthesis of{1S-[4R-(5-chloropyridin-2-yloxy)-2S-(1S-cyclopropylaminooxalylbutyl-carbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl}-carbamicacid tert-butyl ester (18)

Proceeding as described in Example 4 above, but substituting4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid methyl ester hydrochloride with4R-(5-chloropyridin-2-yloxy)pyrrolidine-2-carboxylic acid methyl esterhydrochloride provided the title compound. MS: 622 (M+1).

Example 7 Synthesis of{1S-[4R-(5-chloropyridin-2-yloxy)-2S-(1S-cyclobutylmethyl-2-cyclopropylcarbamoyl-2-oxo-ethylcarbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl}--carbamic acid tert-butyl ester (19)

Proceeding as described in Example 4 above, but substituting4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid methyl ester hydrochloride with4R-(5-chloro-pyridin-2-yloxy)pyrrolidine-2-carboxylic acid methyl esterhydrochloride and(1S-cyclobutylmethyl-2-cyclopropylcarbamoyl-2-hydroxyethyl)-carbamicacid tert-butyl ester in place of[1S-(cyclopropylcarbamoylhydroxymethyl)butyl]carbamic acid tert-butylester provided the title compound. MS: 648 (M+1)

Example 8 Synthesis of1-[2-(3-tert-butylureido)-3,3-dimethyl-butyryl]-4-(5-chloro-pyridin-2-yloxy)-pyrrolidine-2-carboxylicacid (1-cyclopropylaminooxalyl-butyl)-amide (20)

Proceeding as described in Example 3 above but substituting(1S-cyclobutylmethyl-2-cyclopropylcarbamoyl-2-hydroxyethyl)-carbamicacid tert-butyl ester with[1S-(cyclopropyl-carbamoylhydroxymethyl)butyl]carbamic acid tert-butylester provided the title compound. MS: 621 (M+1).

Example 9 Synthesis of1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclopropylaminooxalyl-butyl)-amide (21)

Step 1

Ethyl chloroformate (4.3 mL, 44.5 mmol) was added drop wise at 0° C. toa solution of 3-methoxy cinnamic acid (5.3 g, 29.7 mmol) andtriethylamine (8.3 mL, 59.4 mmol) in acetone (35 mL). After 1 h at 0°C., aqueous sodium azide (3.1 g, 47.5 mmol, 16 mL water) was added dropwise and the reaction mixture was stirred at 23° C. for 16 h. Water (50mL) was added to the mixture and the volatile was removed under vacuo.The resulting slurry was extracted with toluene (3×25 mL) and thecombined organic layers were dried (MgSO₄). The dried solution wasfiltered and added drop wise at 190° C. to a solution of diphenylmethane(25 mL) and tributylamine (14.2 mL, 59.4 mmol). The toluene wasdistilled off as added. After complete addition, the reactiontemperature was raised to 210° C. for 2 h. After cooling, theprecipitated product was collected by filtration and washed with hexanesand dried under vacuum to yield 6-Methoxy-2H-isoquinolin-1-one (1.7 g,9.7 mmol, 33% yield). MS m/z 176 (M⁺+H).

Step 2

A suspension of 6-Methoxy-2H-isoquinolin-1-one (900 mgs, 5.1 mmol) inPOCl₃ (4 mL) was heated at 110° C. for 3 h (clear solution obtained uponheating). After 3 h, the reaction mixture was concentrated under reducedpressure. The residue was poured into iced water (10 mL), pH was thenadjusted to 10 with 3N NaOH and extracted with CHCl₃ (3×25 mL). Thecombined CHCl₃ layers were washed with brine and dried (MgSO₄). Theorganic layer was then filtered, concentrated and purified by flashchromatography (50% ethyl acetate/hexane) to give1-chloro-6-methoxy-isoquinoline (720 mgs, 3.7 mmol, 73% yield) as whitesolid. ¹H NMR (CD₃OD): 8.23 (d, 1 H, J=8.8 Hz); 8.11 (d, 1 H, J=6.0 Hz);7.69 (d, 1 H, J=6.0 Hz); 7.37-7.33 (m, 2H); 3.97 (s, 3H). MS m/z 194(M⁺+H).

Step 3

To commercially available N-t-Boc-(2S, 4R)-hydroxyproline (684 mg, 2.96mmol) in DMSO (20 mL), potassium tert-butoxide (997 mgs, 8.88 mmol) wasadded in small portions, over 15 min at 23° C. The mixture was stirredat 23° C. for 30 min and then cooled to 0° C. At 0° C.,1-chloro-6-methoxy-isoquinoline (600 mgs, 3.11 mmol) was added in smallportions over 10 min. The reaction mixture was stirred at 23° C. for 16h. The resulting suspension was poured into 5% aqueous citric acid (100mL) and extract with EtOAc (3×50 mL). The combined EtOAc layers werewashed with brine and dried (MgSO₄). The organic layer was then filteredand concentrated to give (2S,4R)-(6-Methoxy-isoquinolin-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (1.04 g, 2.68 mmol, 91% yield) as white solid. MS m/z389 (M⁺+H). This material was used in the next step as crude withoutfurther purification.

Step 4

To [1S-(Cyclopropylcarbamoyl-hydroxy-methyl)-butyl]-carbamic acidtert-butyl ester (100 mg, 0.35 mmol) was added 4.0 M HCl in dioxane (10mL). After 1 h, the reaction mixture was concentrated and dried to givethe corresponding HCl salt as a white solid. To the above amine HCl saltin DCM/DMF (8:3. 11.0 mL) was added (2S,4R)-(6-Methoxy-isoquinolin-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (136 mg, 0.35 mmol), HATU (160 mg, 0.42 mmol) andDIPEA (0.2 mL, 1.05 mmol). After 2 h at rt reaction mixture was dilutedwith ethyl acetate and washed with 1N HCl (2×), NaHCO₃ (1×), and brine(1×). The ethyl acetate layer was dried (MgSO₄), filtered and evaporatedto dryness to give2S-[1S-(Cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-4R-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester.

Step 5

To the above crude compound was added 4.0 M HCl in dioxane (10 mL).After 1 h, the reaction mixture was concentrated and dried to give thecorresponding HCl salt as a white solid. To the above amine HCl salt inDCM/DMF (8:3. 11.0 mL) was added2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyric acid (81.0 mg, 0.35 mmol),HATU (160 mg, 0.42 mmol) and DIPEA (0.2 mL, 1.05 mmol). After 16 h atrt, the reaction mixture was diluted with ethyl acetate and washed with1N HCl (2×), NaHCO₃ (1×), and brine (1×). The ethyl acetate layer wasdried (MgSO₄), filtered and evaporated to dryness.

Step 6

The crude product was then dissolved in dry DCM (10.0 mL) andDess-Martin periodinane (223 mg, 0.525 mmol) was added. After stirringat rt for 2 h, the reaction mixture was quenched with 0.26M Na₂S₂O₃ insaturated NaHCO₃ and extracted with ethyl acetate (3×). The combinedethyl acetate layers were then washed with saturated NaHCO₃ (2×) andbrine (1×). Purification by preparative HPLC gave1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclopropylaminooxalyl-butyl)-amide (21) in >95% purity byHPLC. ¹H NMR: (DMSO-d₆) 8.74 (d, 1 H, J=4.8 Hz); 8.28 (d, 1 H, J=7.2Hz); 8.15 (d, 1 H, J=9.2 Hz); 7.97 (d, 1 H, J=6.0 Hz); 7.34-7.32 (m,2H); 7.11-7.08 (m, 1H); 5.94 (brs, 1H); 5.72-5.70 (m, 1H); 5.04-5.00 (m,1H); 4.58 (t, 1 H, J=8.4 Hz); 4.34-4.22 (m, 2H); 3.91 (s, 3H);3.90-3.86(m, 1H); 2.79-2.74 (m, 1H); 2.54-2.51 (m, 1H); 2.18-2.11 (m,1H); 1.77-1.70 (m, 1H); 1.48-1.38 (m, 3H); 1.15 (m, 9H); 0.91 (m, 9H);0.90-0.86 (m, 3H); 0.69-0.56 (m, 4 H). MS m/z 667 (M⁺+H), 689 (M⁺+Na),665 (M⁺−H).

Example 10 Synthesis of1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2S-carboxylicacid (2-cyclopropylcarbamoyl-1S-cyclopropylmethyl-2-oxo-ethyl)-amide(23)

Step 1

To (S)-3-Amino-4,N-dicyclopropyl-2-hydroxy-butyramide HCl salt (47 mg,0.2 mmol) in DCM/DMF (5:1.5, 6.5 mL) was added (2S,4R)-(6-Methoxy-isoquinolin-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (78 mg, 0.2 mmol), HATU (91 mg, 0.4 mmol) and DIPEA(0.1 mL, 0.6 mmol). After 16 h at rt, the reaction mixture was dilutedwith ethyl acetate and washed with 1N HCl (2×), NaHCO₃ (1×), and brine(1×). The ethyl acetate layer was dried (MgSO₄), filtered and evaporatedto dryness to give2S-(2-Cyclopropylcarbamoyl-1S-cyclopropylmethyl-2(±)-hydroxy-ethylcarbamoyl)-4R-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (22).

Step 2

To the above crude compound was added 4.0 M HCl in dioxane (5.0 mL).After 1 h, the reaction mixture was concentrated and dried to give thecorresponding HCl salt as a white solid. To the above amine HCl salt inDCM/DMF (7:3. 10.0 mL) was added2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyric acid (46 mg, 0.2 mmol),HATU (91 mg, 0.24 mmol) and DIPEA (0.1 mL, 0.6 mmol). After 3 h at rt,the reaction mixture was diluted with ethyl acetate and washed with 1NHCl (2×), NaHCO₃ (1×), and brine (1×). The ethyl acetate layer was dried(MgSO₄), filtered and evaporated to dryness.

Step 3

The crude product was then dissolved in dry DCM (8.0 mL) and Dess-Martinperiodinane (127 mg, 0.3 mmol) was added. After stirring at rt for 2 h,the reaction mixture was quenched with 0.26M Na₂S₂O₃ in saturated NaHCO₃and extracted with ethyl acetate (3×). The combined ethyl acetate layerswere then washed with saturated NaHCO₃ (2×) and brine (1×). Purificationby preparative HPLC gave1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2S-carboxylicacid (2-cyclopropylcarbamoyl-1S-cyclopropylmethyl-2-oxo-ethyl)-amide(23) in >95% purity by HPLC. MS m/z 679 (M⁺+H), 701 (M⁺+Na), 677 (M⁺−H).

Example 11 Synthesis of1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carboxylicacid (2-cyclopropylcarbamoyl-1S-cyclopropylmethyl-2S-oxo-ethyl)-amide(26)

Step 1

Ethyl chloroformate (4.3 mL, 44.5 mmol) was added drop wise at 0° C. toa solution of 3-Ethoxy cinnamic acid (5.71 g, 29.7 mmol) andtriethylamine (8.3 mL, 59.4 mmol) in acetone (35 mL). After 1 h at 0°C., aqueous sodium azide (3.1 g, 47.5 mmol, 16 mL water) was addeddropwise and the reaction mixture was stirred at 23° C. for 16 h. Water(50 mL) was added to the mixture and the volatile was removed undervacuo. The resulting slurry was extracted with toluene (3×25 mL) and thecombined organic layers were dried (MgSO₄). The dried solution wasfiltered and added dropwise at 190° C. to a solution of diphenylmethane(25 mL) and tributylamine (14.2 mL, 59.4 mmol). The toluene wasdistilled off as added. After complete addition, the reactiontemperature was raised to 210° C. for 2 h. After cooling, theprecipitated product was collected by filtration and washed with hexanesand dried under vacuum to yield 6-Ethoxy-2H-isoquinolin-1-one (1.92 g,10.2 mmol, 34% yield). MS m/z 190 (M⁺+H).

Step 2

A suspension of 6-Ethoxy-2H-isoquinolin-1-one (896 mg, 4.74 mmol) inPOCl₃ (4 mL) was heated at 110° C. for 3 h (clear solution obtained uponheating). After 3 h, the reaction mixture was concentrated under reducedpressure. The residue was poured into iced water (10 mL), pH was thenadjusted to 10 with 3N NaOH and extracted with CHCl₃ (3×25 mL). Thecombined CHCl₃ layers were washed with brine and dried (MgSO₄). Theorganic layer was then filtered and concentrated to give1-chloro-6-ethoxy-isoquinoline (866 mg, 4.18 mmol, 88% yield, >90% pure)as tan solid. MS m/z 208 (M⁺+H).

Step 3

To commercially available N-t-Boc-(2S, 4R)-hydroxyproline (531 mg, 2.30mmol) in DMSO (20 mL), potassium tert-butoxide (774 mg, 6.9 mmol) wasadded in small portions, over 15 min at 23° C. The mixture was stirredat 23° C. for 30 min and then cooled to 0° C. At 0° C.,1-chloro-6-ethoxy-isoquinoline (500 mgs, 2.41 mmol) was added in smallportions over 10 min. The reaction mixture was stirred at 23° C. for 16h. The resulting suspension was poured into water and the mixture waswashed with ether (2×) and ethylacetate (2×). The aqueous layer wasacidified with aqueous 1N HCl to pH ˜4 and extracted with DCM (3×). Thecombined DCM layers were washed with brine and dried (MgSO₄). Theorganic layer was then filtered, and concentrated to give (2S,4R)-(6-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (24) (crude wt=1.18 g,>90% pure). MS m/z 403 (M⁺+H),401 (M⁺−H), 303 (M⁺−Boc). This material was used in the next step ascrude without further purification.

Step 4

To (S)-3-Amino-4,N-dicyclopropyl-2-hydroxy-butyramide HCl salt (66 mgs,0.28 mmol) in DCM/DMF (10:3, 13 mL) was added (2S,4R)-(6-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (114 mgs, 0.28 mmol), HATU (128 mg, 0.34 mmol) andDIPEA (0.15 mL, 0.84 mmol). After 1 h at rt, the reaction mixture wasdiluted with ethyl acetate and washed with 1N HCl (2×), NaHCO₃ (1×), andbrine (1×). The ethyl acetate layer was dried (MgSO₄), filtered andevaporated to dryness to give2S-(2-Cyclopropylcarbamoyl-1S-cyclopropylmethyl-2-hydroxy-ethylcarbamoyl)-4R-(6-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (25).

Step 5

To the above crude compound was added 4.0 M HCl in dioxane (10 mL).After 1 h, the reaction mixture was concentrated and dried to give thecorresponding HCl salt as a white solid. To the above amine HCl salt inDCM/DMF (10:3, 13 mL) was added2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyric acid (64 mgs, 0.28 mmol),HATU (128 mg, 0.34 mmol) and DIPEA (0.15 mL, 0.84 mmol). After 1 h atrt, the reaction mixture was diluted with ethyl acetate and washed with1N HCl (2×), NaHCO₃ (1×), and brine (1×). The ethyl acetate layer wasdried (MgSO₄), filtered and evaporated to dryness.

Step 6

The crude product was then dissolved in dry DCM (10.0 mL) andDess-Martin periodinane (154 mgs, 0.364 mmol) was added. After stirringat rt for 1 h, the reaction mixture was quenched with 0.26M Na₂S₂O₃ insaturated NaHCO₃ and extracted with EtOAc (3×). The combined EtOAclayers were then washed with saturated NaHCO₃ (2×), brine (1×) and dried(MgSO₄). The organic layer was then filtered, concentrated and purifiedby flash chromatography (65% ethyl acetate/hexane) to give1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carboxylicacid (2-cyclopropylcarbamoyl-1S-cyclopropylmethyl-2S-oxo-ethyl)-amide(26) (80.7 mg, 0.116 mmol, 42% yield) as white solid. ¹H NMR: (DMSO)8.67 (d, 1 H, J=5.6 Hz); 8.26 (d, 1 H, J=6.8 Hz); 8.06 (d, 1 H, J=8.8Hz); 7.89 (d, 1 H, J-5.6 Hz); 7.24-7.22 (m, 1H); 7.01-6.98 (dd, 1 H,J=2.4, 8.8 Hz); 5.90-5.85 (m, 2H); 5.65-5.62 (m, 1H); 5.06-5.01 (m, 1H);4.53 (t, 1 H, J=8.0 Hz); 4.26-4.23 (m, 1H); 4.16-4.08 (m, 3H); 3.84-3.80(m, 1H); 2.69-2.65 (m, 1 H); 2.11-2.04 (m, 1H); 1.64-1.57 (m, 1H);1.35-1.29 (m, 3H); 1.15 (m, 9H); 0.91 (m, 9H); 0.89-0.81 (m, 3H);0.61-0.48 (m, 4H); 0.36-0.27 (m, 2H). MS m/z 693 (M++H), 715 (M⁺+Na),691 (M⁺−H).

Example 12 Synthesis of1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclopropylaminooxalyl-butyl)-amide (28)

Step 1

To [1S-(Cyclopropylcarbamoyl-hydroxy-methyl)-butyl]-carbamic acidtert-butyl ester (75 mg, 0.26 mmol) was added 4.0 M HCl in dioxane (6.0mL). After 1 h, the reaction mixture was concentrated and dried to givethe corresponding HCl salt as a white solid. To the above amine HCl saltin DCM/DMF (10:3, 13 mL) was added (2S,4R)-(6-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (106 mgs, 0.26 mmol), HATU (119 mg, 0.31 mmol) andDIPEA (0.15 mL, 0.78 mmol). After 1 h at rt reaction mixture was dilutedwith ethyl acetate and washed with 1N HCl (2×), NaHCO₃ (1×), and brine(1×). The ethyl acetate layer was dried (MgSO₄), filtered and evaporatedto dryness to give2S-[1S-(Cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-4R-(6-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (27).

Step 2

To the above crude compound was added 4.0 M HCl in dioxane (10 mL).After 1 h, the reaction mixture was concentrated and dried to give thecorresponding HCl salt as a white solid. To the above amine HCl salt inDCM/DMF (10:3, 13 mL) was added2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyric acid (60 mgs, 0.26 mmol),HATU (128 mg, 0.34 mmol) and DIPEA (0.15 mL, 0.84 mmol). After 1 h atrt, the reaction mixture was diluted with ethyl acetate and washed with1N HCl (2×), NaHCO₃ (1×), and brine (1×). The ethyl acetate layer wasdried (MgSO₄), filtered and evaporated to dryness.

Step 3

The crude product was then dissolved in dry DCM (10.0 mL) andDess-Martin periodinane (143 mgs, 0.338 mmol) was added. After stirringat rt for 1 h reaction mixture was quenched with 0.26M Na₂S₂O₃ insaturated NaHCO₃ and extracted with ethyl acetate (3×). The combinedethylacetate layers were then washed with saturated NaHCO₃ (2×), brine(1×) and dried (MgSO₄). The organic layer was then filtered,concentrated and purified by flash chromatography (65% ethylacetate/hexane) to give1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclopropylaminooxalyl-butyl)-amide (28) (75.7 mg, 0.11 mmol,43% yield) as white solid. ¹H NMR: (DMSO-d₆) 8.75 (d, 1 H, J=4.8 Hz);8.28 (d, 1 H, J=7.2 Hz); 8.13 (d, 1 H, J=8.8 Hz); 7.96 (d, 1 H, J=6.0Hz); 7.31-7.29 (m, 2H); 7.10-7.06 (dd, 1 H, J=2.4, 9.2 Hz); 5.94-5.92(m, 2H); 5.72-5.70 (m, 1H); 5.04-5.00 (m, 1H); 4.58 (t, 1 H, J=7.6 Hz);4.34-4.30 (m, 1H); 4.23-4.17 (m, 3H); 3.90-3.86 (m, 1H); 2.79-2.74 (m,1H); 2.54-2.51 (m, 1 H); 2.18-2.11 (m, 1H); 1.77-1.70 (m, 1H); 1.48-1.38(m, 3H); 1.15 (m, 9H); 0.91 (m, 9H); 0.89-0.86 (m, 3H); 0.69-0.59 (m,4H). MS m/z 681 (M⁺+H), 703 (M⁺+Na), 679 (M⁺−H).

Example 13 Synthesis of1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclopropylaminooxalyl-pentyl)-amide (30)

Step 1

To (S)-3-Amino-2-hydroxy-heptanoic acid cyclopropylamide HCl salt (96mgs, 0.40 mmol) in DCM/DMF (10:3, 13 mL) was added (2S,4R)-(6-Methoxy-isoquinolin-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (157 mgs, 0.40 mmol), HATU (200 mg, 0.53 mmol) andDIPEA (0.35 mL, 2.0 mmol). After 1 h at rt reaction mixture was dilutedwith ethyl acetate and washed with 1N HCl (2×), NaHCO₃ (1×), and brine(1×). The ethyl acetate layer was dried (MgSO₄), filtered and evaporatedto dryness to give2S-[1S-(Cyclopropylcarbamoyl-(±)-hydroxy-methyl)-pentylcarbamoyl]-4R-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (29). MS m/z 571 (M⁺+H), 593 (M⁺+Na), 569 (M⁺−H),471 (M⁺−Boc).

Step 2

To the above crude compound was added 4.0 M HCl in dioxane (10 mL).After 1 h at rt, the reaction mixture was concentrated and dried to givethe corresponding HCl salt as a white solid. To the above amine HCl saltin DCM/DMF (10:3, 13 mL) was added25-(3-tert-Butyl-ureido)-3,3-dimethyl-butyric acid (93 mgs, 0.40 mnmol),HATU (200 mg, 0.53 mmol) and DIPEA (0.35 mL, 2.0 mmol). After 1 h at rtreaction mixture was diluted with ethyl acetate and washed with 1N HCl(2×), NaHCO₃ (1×), and brine (1×). The ethyl acetate layer was dried(MgSO₄), filtered and evaporated to dryness. MS m/z 683 (M⁺+H), 705(M⁺+Na), 681 (M⁺−H).

Step 3

The crude product was then dissolved in dry DCM (10.0 mL) andDess-Martin periodinane (223 mgs, 0.53 mmol) was added. After stirringat rt for 2 h reaction mixture was quenched with 0.26M Na₂S₂O₃ insaturated NaHCO₃ and extracted with ethyl acetate (3×). The combinedethylacetate layers were then washed with saturated NaHCO₃ (2×), brine(1×) and dried (MgSO₄). The organic layer was then filtered,concentrated and purified by flash chromatography (45% ethylacetate/hexane) to give1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclopropylaminooxalyl-pentyl)-amide (30) (83.5 mg, 0.12 mmol,31% yield) as white solid. ¹H NMR: (DMSO) 8.74 (d, 1 H, J=4.8 Hz); 8.27(d, 1 H, J=7.2 Hz); 8.15 (d, 1 H, J=9.2 Hz); 7.97 (d, 1 H, J=6.0 Hz);7.33-7.31 (m, 2H); 7.10-7.08 (dd, 1 H, J=2, 8.8 Hz); 5.96 (s, 1H); 5.94(d, 1 H, J=9.6 Hz); 5.71-5.69 (m, 1H); 5.02-4.98 (m, 1H); 4.60 (t, H,J=8.4 Hz); 4.34-4.22 (m, 1H); 4.23 (d, 1 H, J=9.2 Hz); 3.91 (s, 3H);3.90-3.87 (m, 1H); 2.78-2.73 (m, 1H); 2.54-2.51 (m, 1H); 2.17-2.11 (m,1H); 1.77-1.72 (m, 1H); 1.43-1.33 (m, 5H); 1.20 (m, 9H); 0.95 (m, 9H);0.88-0.85 (m, 5H); 0.69-0.58 (m, 4H). MS m/z 681 (M⁺+H), 703 (M⁺+Na),680 (M⁺−H).

Example 14

Step 1

3-Cyclopropyl-6-methoxyisoquinoline (32). Lithium tetramethylpiperididewas prepared by the treatment of 2,2,6,6-tetramethylpiperidine (1.0 g;7.0 mmol) in THF (17 mL) with n-BuLi (1.6 M in hexanes; 8.0 mmol)dropwise at −15° C. After 15 min at −15° C., a solution ofcyclohexyl(4-methoxy-2-methylbenzylidene)amine (660 mg; 2.86 mmol) inTHF (3 mL) was added dropwise to give a purple solution. The reactionmixture was allowed to warm to 0° C. over a 20-min period then asolution of N-methyl-N-methoxycyclopropanecarboxamide (630 mg: 4.4 mmol)in THF (2 mL) was added in one portion while at 0° C. The reactionmixture was kept at room temperature for 30 min and then added tosaturated aq. NH₄Cl. The solution was extracted with diethyl ether andthe organic phase was washed with saturated aq. NaCl, dried andconcentrated in vacuo.

The residue was dissolved in concentrated NH₄OH (15 mL) and treated withacetic acid (1 mL) then heated to reflux. The mixture was diluted withwater, and the resulting solution extracted with diethyl ether. Theether extracts were washed with water, and saturated aq. NaCl, thendried and concentrated in vacuo. Chromatography (SiO₂; 4:1 hexane/EtOAc)provided 160 mg (28%) of the title compound. Execution of the processwith 1.5 g of the imine provided 400 mg (30%) of the title compound.

Step 2

1-Chloro-3-cyclopropyl-6-methoxy-isoquinoline (34).3-Cyclopropyl-6-methoxyisoquinoline (32) was dissolved indichloromethane (8 mL) and cooled to 0° C. This solution was treatedwith a solution of m-chloroperbenzoic acid (mCPBA; 412 mg; 2.4 mmol) indichloromethane (8 mL) and the mixture was stirred for 2 h at RT. Thereaction mixture was quenched with dimethyl sulfide (100 μL) and stirredfor another 15 min. The mixture was treated with saturated aq. sodiumbicarbonate (20 mL) and the layers were separated. The aq. phase wasextracted with dichloromethane and the combined organic phases weredried, concentrated in vacuo and chromatographed (SiO₂; 10% MeOH inCH₂Cl₂) to give 405 mg (94%) of the N-oxide of3-cyclopropyl-6-methoxyisoquinoline (33).

The N-oxide was dissolved in dichloromethane (5 mL) and 1 mL of POCl₃was added. The mixture was heated at reflux for 2 h, cooled and pouredonto ice. The mixture was treated with NH₄OH to pH 8 and the resultingsolution was extracted with ethyl acetate. The organic phase was washedwith sat. aq. NaCl, dried and concentrated in vacuo. The crude productwas purified by chromatography (SiO₂; Hexane/EtOAc, 4:1) to provide 310mg (66% overall) of the title compound.

Step 3

1-N-BOC-4-(3-Cyclopropyl-6-methoxyisoquinolin-1-yloxy)pyrrolidine-2-carboxylicacid (37). N-BOC-4-hydroxy-L-proline (A; 192 mg; 830 μmol) was dissolvedin DMSO (5 mL) at RT then potassium t-butoxide (270 mg; 2.4 mrnol) wasadded. The resulting solution was stirred at RT for 1.5 h then1-Chloro-3-cyclopropyl-6-methoxyisoquinoline (4; 192 mg; 820 μmol) wasadded. The resulting solution was stirred overnight, diluted with 15 mLof 5% aq. citric acid and extracted with ethyl acetate. The organicphase was washed with sat. aq. NaCl, dried and concentrated in vacuo togive 375 mg of the crude arylether of N-BOC-4-hydroxy-L-proline (35).

The crude aryl ether was dissolved in DMF (2 mL) and(O-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU; 380 mg; 830 μmol) was added followed by3-(S)-amino-2-(RS)-hydroxyhexanoic acid-N-cyclopropylcarboxamidehydrochloride (36; 190 mg; 830 μmol) and N,N-diisopropylethylamine(DIPEA; 800 μL). The resulting mixture was stirred overnight thendiluted with water. The resulting precipitate was filtered, washed withwater and dried to give 460 mg (93%) of the title compound (37).

Step 4

(S)-1-[2-(3-tert-Butylureido)-3,3-dimethylbutyryl]-4-trans-(3-cyclopropyl-6-methoxyisoquinolin-1-yloxy)pyrrolidine-2-(S)-carboxylicacid (1-cyclopropylaminooxalyl-butyl)amide Hydrochloride (40). Compound37 was dissolved in 4N HCl in 1,4-dioxane (2 mL) and stirred 1 h at RT.The reaction mixture was concentrated in vacuo and the residue (compound38) was dissolved in DMF (2 mL). The solution was treated with(S)-2-(3-tert-butylureido)-3,3-dimethylbutyric acid (C; 100 mg; 440μmol), HATU (200 mg; 520 μmol), and DIPEA (800 mL). The reaction mixturewas diluted with water and the resulting precipitate was filtered,washed with water and dried to give 250 mg (80%) of the corresponding2-hydroxycarboxamide 39. The solid was dissolved in dichloromethane (20mL) and treated with1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (D; 220 mg;660 μmol). The reaction mixture was stirred for 2h at RT. The solutionwas diluted with diethyl ether (40 mL) followed by the addition ofsaturated aq. Na₂S₂O₃ (10 mL) and 10 mL of aq. NaHCO₃ (10 mL). Thebiphasic mixture was stirred for 10 min and the layers were separated.The organic phase was washed with saturated aq. NaCl, dried andconcentrated in vacuo. The residue was purified by chromatography (SiO₂;Hexane/EtOAc, 1:1) then the isolated material was lyophilized fromacetonitrile and 0.01% aq. HCl to give 150 mg (46%) of the titlecompound (40) as the HCl salt. Mass Spec (M+Na) 705.

Example 15

Step 1

4-Acetyl-6-methoxyisochroman-1,3-dione (42). Following a literatureprocedure (Ind. J Chem. Sec. B, 1986, 25B, 640-643),2-carboxymethyl-4-methoxybenzoic acid (41; 1.0 g; 4.8 mmol) wasdissolved in a mixture of pyridine (1.4 mL) and acetic anhydride (8.6mL; 9.3 g; 91 mmol) then stirred for 3 h during which time a solid hadformed. The suspension was diluted with diethyl ether, filtered and thefilter cake washed with diethyl ether. Yield: 905 mg (81%) of the titlecompound.

Step 2

6-Methoxy-3-methyl-2H-isoquinolin-1-one (43). Cyclic anhydride 42 (405mg; 1.73 mmol) was dissolved in aqueous NH₄OH and heated at reflux for1.5 h. The mixture was cooled to RT and the solid was filtered thendried overnight to give 270 mg (74%) of the title compound.

Step 3

1-Chloro-6-methoxy-3-methylisoquinoline (44). Isoquinoline-1-one 43 wasdissolved in POCl₃ (2.5 mL) and heated at reflux for 1h. The excessPOCl₃ was removed in vacuo and the residue was dissolved in CHCl₃. Theresulting solution was washed with 1N aq. NaOH, water and saturated ag.NaCl. Evaporation of the solvent gave crude 44 which was used directlyin the next step.

Step 4

1-N-BOC-4-(6-Methoxy-3-methylisoquinolin-1-yloxy)pyrrolidine-2-carboxylicacid (45). N-BOC-4-hydroxy-L-proline (A; 281 mg; 1.21 mmol) wasdissolved in DMSO (3 mL) at RT then potassium t-butoxide (270 mg; 2.4mmol) was added. The resulting solution was stirred at RT for 2 h thencooled to 0° C. Next a solution of isoquinoline 14 in DMSO (3 mL) wasadded dropwise to the cold solution of A and t-BuOK, then the mixturewas allowed to warm up to RT. The solution was stirred for 16 h, and anaddition 0.2 equivalents of A was added and the mixture stirred for anadditional 1.5 h. The reaction mixture was acidified to pH=4 with 5% aq.citric acid. The solution was extracted with ethyl acetate and theorganic phase washed with water followed by saturated aq. NaCl. Theorganic phase was concentrated in vacuo to give the title compound.

Step 5

1-N-BOC-2-[1-(Cyclopropylcarbamoylhydroxymethyl)butylcarbamoyl]-4-(6-methoxy-3-methyl-isoquinolin-1-yloxy)pyrrolidine(47). Compound 45 (196 mg; 487 μmol) was converted to the title compoundaccording to the same process described for compound 5. Pyrrolidine 47(210 mg; 77% yield) was used in the subsequent step without furtherpurification.

Step 6

1-[2-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4-(3-methyl-6-methoxyisoquinolin-1-yloxy)-pyrrolidine-2-carboxylicacid (1-cyclopropylaminooxalylbutyl)-amide (50). Compound 47 (210 mg;368 μmol) was converted to the corresponding HCl salt as described forcompound 48. The HCl salt 48 was then converted to the tripeptide 49with intermediate C and HATU using the same conditions employed forcompound 39. Finally 49 was converted to the title compound, α-ketoamide50 employing D in dichloromethane according to the same procedure giveabove for the conversion of 39 to 40. Purification of the crude productby chromatography (SiO₂; 45% ethyl acetate in hexane) provided 85 mg of50 (34% from 17). Mass Spec (M +) 680.

Example 16 Synthesis of1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)pyrrolidine-2S-carboxylicacid(1S-cyclopropylaminooxalyl-butyl)-amide(1):

Alternative route for compound 7

Step 1

A suspension of 4-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline (Faber K.etal., J. Heterocyclic chem., 1985 22, 1080) (5.0 g, 26.17 mmol) inPOCl₃ (25 mL, 261.7 mmol) was heated at 115° C. for 3 h (clear solutionobtained upon heating). After 3 h, the reaction mixture was concentratedunder reduced pressure. The residue was poured into iced water (40 mL),pH was then adjusted to 10 with 3N NaOH and extracted with CHCl₃ (3×100mL). The combined CHCl₃ layers were washed with brine and dried (MgSO₄).The organic layer was then filtered and concentrated to give2,4-Dichloro-7-methoxy-quinoline (4.9 g, 21.49 mmol, 82% yield) as brownsolid. MS m/z 229 (M⁺+H).

Step 2

Solid pyrazole (3.2 g, 47.36 mmol, 3.0 equiv.) was heated and melted at80° C. Then solid 2,4-Dichloro-7-methoxy-quinoline (3.6 g, 15.78 mmol,1.0 equiv.) was added and the mixture was then heated to 115° C. fo 3 h.Then the mixture was cooled to rt and purified by flash chromatography(20% ethyl acetate/hexane) to give4-Chloro-7-methoxy-2-pyrazol-1-yl-quinoline (2.3 g, 8.88 mmol, 56%yield) as white solid. ¹H NMR (CDCl₃): 8.77 (d, 1 H, J=2.8 Hz); 8.18 (s,1H); 8.10 (d, 1 H, J=9.2 Hz); 7.79 (s, 1H); 7.38 (d, 1 H, J=2.8 Hz);7.23 (dd, 1 H, J=2.0, 8.8 Hz); 6.53-6.52 (m, 1H); 3.98 (s, 3H). MS m/z260 (M⁺+H).

Step 3

To commercially available N-t-Boc-(2S, 4R)-hydroxyproline (1.53 g, 6.64mmol) in DMSO (20 mL), potassium tert-butoxide (1.9 g, 16.6 mmol) wasadded in small portions, over 15 min at 23° C. The mixture was stirredat 23° C for 1.5 h and then 4-Chloro-7-methoxy-2-pyrazol-1-yl-quinoline(1.9 g, 7.30 mmol) was added in small portions over 15 min. The reactionmixture was stirred at 23° C. for 16 h. The resulting suspension waspoured into water (150 mL) and the mixture was washed with ethylacetate(2×100 mL). The aqueous layer was acidified with aqueous 1N HCl to pH ˜4and extracted with CHCl₃ (3×100 mL). The combined CHCl₃ layers werewashed with brine and dried (MgSO₄). The organic layer was thenfiltered, and concentrated to give (2S,4R)-(7-Methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (2.7 g, 5.95 mmol, 90% yield). MS m/z 455(M⁺+H), 453 (M⁺−H), 355 (M⁺−Boc). This material was used in the nextstep as crude without further purification.

Step 4

To [1S-(Cyclopropylcarbamoyl-hydroxy-methyl)-butyl]-carbamic acidtert-butyl ester (1.05 g, 3.67 mmol) was added 4.0 M HCl in dioxane (13mL). After 1 h, the reaction mixture was concentrated and dried to givethe corresponding HCl salt as a white solid. To the above amine HCl saltin DCM/DMF (3:1, 60 mL) was added (2S,4R)-(7-Methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (1.66 g, 3.67 mmol), HATU (1.67 g, 4.40 mmol)and DIPEA (2.6 mL, 14.08 mmol). After 1 h at rt, the reaction mixturewas diluted with ethyl acetate (100 mL) and washed with 1N HCl (2×50mL), NaHCO₃ (1×100 mL) and brine (1×). The ethyl acetate layer was dried(MgSO₄), filtered and evaporated to dryness to give2S-[1S-(Cyclopropylcarbamoyl-hydroxy-methyl)-butylcarbamoyl]-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester as mixture of diastereomers. This material wasused in the next step as crude without further purification.

Step 5

To the above compound was added 4.0 M HCl in dioxane (15 mL). After 1 h,the reaction mixture was concentrated and dried to give thecorresponding HCl salt as a white solid. To the above amine HCl salt inDCM/DMF (3:1, 60 mL) was added2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyric acid (848 mg, 3.67 mmol),HATU (1.67 g, 4.40 mmol) and DIPEA (2.6 mL, 14.08 mmol). After 1 h atrt, the reaction mixture was diluted with ethyl acetate (100 mL) andwashed with 1N HCl (2×50 mL), NaHCO₃ (1×100 mL), and brine (1×). Theethyl acetate layer was dried (MgSO₄), filtered and evaporated todryness. This material was used in the next step as crude withoutfurther purification.

Step 6

The above crude product was then dissolved in dry DCM (25 mL) andDess-Martin periodinane (2.0 g, 4.71 mmol) was added. After stirring atrt for 1 h reaction mixture was quenched with 0.26M Na₂S₂O₃ in saturatedNaHCO₃ and extracted with DCM (3×). The combined DCM layers were thenwashed with saturated NaHCO₃ (2×), brine (1×) and dried (MgSO₄). Theorganic layer was then filtered, concentrated and purified by flashchromatography (60% ethyl acetate/hexane) to give1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)pyrrolidine-2S-carboxylicacid (1S-cyclopropylainnooxalyl-butyl)-amide (7) (1.6 g, 2.18 mmol, 60%yield) as white solid. ¹H NMR: (DMSO-d₆) 8.76-8.70 (m, 2H); 8.22 (d,J=6.8 Hz, 1H); 8.11 (d, J=9.6 Hz, 1H); 7.87 (d, J=1.2 Hz, 1H); 7.45 (s,1H); 7.27 (d, J=2.4 Hz, 1H); 7.00-6.97 (dd, J=2.8 and 9.6 Hz, 1H);6.64-6.62 (m, 1H); 5. 92 (brs, 1H); 5.49 (brs, 1H); 5.00-4.96 (m, 1H);4.55-4.49 (m, 2H); 4.18 (d, J=5.6 Hz, 1H); 3.90 (s, 3H); 3.91-3.82 (m,1H); 3.54 (brs, 1H); 2.75-2.72 (m, 1H); 2.54-2.51 (m, 1H); 2.17-2.14 (m,1H); 1.69-1.66 (m, 1H); 1.40-1.34 (m, 3H); 1.13 (m, 9H); 0.93 (m, 9H);0.90-0.82 (m, 3H); 0.65-0.53 (m, 4H). MS m/z 733 (M⁺+H), 755 (M⁺+Na),731 (M⁺−H).

Biological Examples Example 1 HCV Replicon Assay

The HCV replicon assay is a cell-culture system that mimics in vivo HCVreplication and provides a system to study HCV replication in vitro. Itwas created by transfecting cloned viral RNA derived from a consensusHCV genornic sequence into human Huh7 hepatoma cells that aresemi-permissive for viral RNA production (Lohmann V., Korner F., Koch J.-O., Herian U., Theilmann L. and Bartenschlager R. (1999). Replicationof subgenomic Hepatitis C virus RNAs in a hepatoma cell line. Science285, 110-113 and Blight K. J., Kolykhalov A. A. and Rice C. M. (2000).Efficient initiation of HCV RNA Replication in cell culture. Science290, 972-1974). These transfected cell lines contain a subgenomic HCVRNA genome that includes (1) the HCV 5′NTR fused to 12 amino acids ofthe capsid coding region, (2) the neomycin phosphotransferase gene (Neo)as a selectable marker, (3) the internal ribosome entry site (IRES) fromencephalomyocarditis virus (EMCV) that directs translation of HCVnon-structural proteins (variously NS2 or NS3 to NS5B), and (4) the3′NTR. Replicon-containing cells autonomously and persistently replicateHCV RNA that can be measured quantitatively by real-time qPCR.Therefore, the replicon system facilitates quantitative assessment ofanti-viral activity by monitoring changes in HCV RNA replication in acell-based assay.

HCV replicon-containing cells (Huh7/Clone A) were routinely maintainedin Clone A growth medium (DMEM medium [Invitrogen], supplemented with10% Fetal Bovine Serum, 1% Non Essential Amino Acids and 1g/L G418).Test compounds were dissolved in dimethyl sulfoxide (DMSO) to make 200×stock solutions for all doses prior to treatment.

For the HCV replicon assay, Huh7/Clone A cells were trypsinized fromculture flasks, seeded in 1 ml of Clone A growth medium without G418 at4×10⁴ cells per well in 24-well plates and incubated at 37° C. in ahumidified CO₂ (5%) incubator overnight. Following overnight incubation,compound solutions were added into wells in the same volume (5 μl of200× compound stock per well) to give a final DMSO concentration of0.5%. Three wells on each plate supplemented with 5 μl of DMSO served asuntreated controls. For IC₅₀ determinations, compounds were tested at 7serial dilutions in triplicates from the starting stock solutions. Theplates were incubated at 37° C. for 48 hours. After incubation, cellswere harvested, transferred to 96-well plates, and subjected to totalRNA extraction using the RNA Isolation Kit (RNeasy 96, Qiagen) accordingto the protocol described by the manufacture's RNeasy 96 Handbook(Qiagen).

Total RNA eluted in 130 μl of RNase-free dH₂O was quantitated by theRiboGreen Assay according to the supplier's protocol (Molecular Probe).Briefly, 5 μl of RNA samples were aliquoted in duplicate to a 96-wellblack microplate and a 96-well TaqMan Optical plate. RNA samples in theblack microplate were mixed with 95 μl of diluted RiboGreen reagent(1:250 dilution in TE buffer) and sample fluorescence was measured usinga fluorescence microplate reader at standard fluorescein wavelengths(excitation ˜480 nm, emission ˜520 nm). Ribosomal RNA (Molecular Probe)was used as standard.

TaqMan quantitative PCR (RT-qPCR) was used to quantitate the amount ofHCV replicon RNA in each sample. The RT-qPCR reactions were performed in25 μl on an ABI PRISM 7900 HT Sequence Detection System (AppliedBiosystems). The reaction mixture contained 5 μl of total RNA (10-100ng), 1 X TaqMan Buffer A (Applied Biosystems), 5.5 mM MgCl₂, 1.2 mM dNTPmix, 0.625 U of AmpliTaq Gold (Applied Biosystems), 5U of MMLV reversetranscriptase (Promega), 5 U of rRNasin (Promega), 300 nM each of theforward and reverse primers, and 100 nM TaqMan MGB probe. Primers andprobe were designed to hybridize to a portion of the neomycin resistancegene (neo) in the replicon and the sequences are as follows: forwardprimer 5′- GGCTACCTGCCCATTCGA -3′ (SEQ ID NO:1); reverse primer 5′-CCGGCTTCCATCCGAGTAC -3′ (SEQ ID NO:2); MGB probe 5′- CCACCAAGCGAAACA -3′(SEQ ID NO:3). The RT step was performed at 48° C. for 30 min, followedby 10 min at 95° C. The thermal cycling program consisted of 40 cyclesof 15 s at 95° C. and 1 min at 60° C. TaqMan raw data (Ct values) wereanalyzed using the Sequence Detection System (SDS) software,mathematically converted to HCV RNA genome amount and normalized tototal RNA in each sample. The sample without compound treatment servedas a control and the HCV replicon RNA level from untreated cells wasdefined as 100%. Compound inhibitory activity was determined as theratio of the normalized HCV RNA amount in treated samples relative tothe untreated control. Compound IC₅₀s were calculated using a standard 4parameter curve fit model.

Compounds of the invention were tested by the above-described assay andobserved to inhibit HCV replication with IC₅₀'s<100 micromolar.Compounds 3, 6 and 7 inhibited HCV replication with IC₅₀'s<50micromolar; while compounds 1, 2, 5, 8-13 and 15 inhibited HCVreplication with IC₅₀'s<10 micromolar.

Example 1

Representative pharmaceutical formulations containing a Compound ofFormula (I)

ORAL FORMULATION Compound of Formula (I) 10-100 mg Citric AcidMonohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL

INTRAVENOUS FORMULATION Compound of Formula (I) 0.1-10 mg DextroseMonohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05 mg SodiumHydroxide 0.18 mg Water for Injection q.s. to 1.0 mL

TABLET FORMULATION Compound of Formula (I) 1% Microcrystalline Cellulose73% Stearic Acid 25% Colloidal Silica 1%

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

1. A compound of Formula (I):

wherein E is —COCONR⁵R⁶, —COCF₂CONR⁵R⁶, —COCF₂C(O)OR⁵, —COCOR⁷,—COCF₂R⁸, —COR⁹, or —B(OR¹³)₂ where R⁵, R⁶, R⁷, R⁹, and each R¹³ isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, or heterocyclylalkyl and R⁸ is halo, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl wherein the aliphatic,alicyclic and aromatic groups in E are optionally substituted with one,two, or three R^(a) independently selected from hydroxy, alkoxy,haloalkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio,amino, monosubstituted amino, disubstituted amino, alkylsulfonyl,arylsulfonyl, carboxy, alkoxycarbonyl, alkenyloxycarbonyl,alkynyloxycarbonyl, alkenylaminocarbonyl, acylamino, aminocarbonyl,halo, or cyano and further wherein the aromatic or alicyclic ring inR^(a) is optionally substituted with one, two, or three substituentsindependently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy,carboxy, or carboxyalkyl; R¹ is alkyl, haloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl wherein the aliphatic, alicyclic andaromatic groups in R¹ are optionally substituted with one or two R^(b)independently selected from hydroxy, alkoxy, aryloxy, heteroaryloxy,alkylthio, arylthio, heteroarylthio, amino, monosubstituted amino,disubstituted amino, alkylsulfonyl, arylsulfonyl, carboxy,alkoxycarbonyl, acylamino, aminocarbonyl, halo, or cyano and furtherwherein the aromatic ring in R^(b) is optionally substituted with one,two, or three substituents independently selected from alkyl, alkoxy,halo, haloalkyl, haloalkoxy, cyano, carboxy, or carboxyalkyl; X is —O—,—NH—, —S—, —SO—, or —SO₂—; R³ is alkyl, haloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl wherein the aliphatic, alicyclic andaromatic groups in R³ are optionally substituted with one or two R^(c)independently selected from hydroxy, alkoxy, haloalkoxy, aryloxy,heteroaryloxy, alkylthio, arylthio, heteroarylthio, amino,monosubstituted amino, disubstituted amino, alkylsulfonyl, arylsulfonyl,carboxy, alkoxycarbonyl, acylamino, aminocarbonyl, halo, or cyano andfurther wherein the aromatic ring in R^(c) is optionally substitutedwith one, two, or three substituents independently selected from alkyl,alkoxy, halo, haloalkyl, haloalkoxy, carboxy, or carboxyalkyl; Y is—C(O)NH—, —OC(O)NH—, —NR¹⁴—C(O)NH—, or —NR¹⁴C(O)O— where each R¹⁴ isselected from hydrogen, alkyl optionally substituted with halo, hydroxy,alkoxy, amino, monosubstituted amino, disubstituted amino, aryl,heteroaryl or heterocyclyl; R² is a group of formula (a):

where R^(d1) is hydrogen, hydroxy, alkoxy, amino, alkylamino,dialkylamino, haloalkoxy or alkylsulfonyl; R^(d) and R^(d2) areindependently hydrogen, alkyl, halo, alkoxy, alkvlthio, oralkylsulfonyl; or R^(d1) and R^(d) or R^(d1) and R^(d2) together withthe carbon atoms to which they are attached form a 4, 5, or 6- atomheterocyclyl ring wherein one or two ring atoms are replaced by oxygenor —N— where the heterocyclyl ring is optionally substituted with one ortwo alkyl; R^(d3) is aryl, heteroaryl, or heterocyclyl optionallysubstituted with halo, alkyl, cycloalkyl, cycloalkylalkyl, alkoxy,cycloalkoxy, nitro, alkylcarbonylamino, cycloalkylcarbonylamino,cycloalkylalkycarbonylamino, alkyloxycarbonylamino, amino, alkylamino,dialkylamino, or —NHCONRR′ where R is hydrogen or alkyl and R′ ishydrogen, alkyl, cycloalkyl, or cycloalkylalkyl wherein cycloalkyl andcycloalkylalkyl are optionally substituted with one, two or three alkyl;and R⁴ is selected from the group consisting of alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl,and heterocyclylalkyl; provided that: (i) when R⁴ is alkyl and when Y is—C(O)NH —, then R^(d3) is a heteroaryl ring; and (ii) when R⁴ iscycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, or heterocyclylalkyl, then R^(d3) is a heteroaryl ring;wherein the aromatic or alicyclic ring in R⁴ is optionally substitutedwith one, two, or three R^(f) independently selected from alkyl, alkoxy,halo, haloalkyl, haloalkoxy, carboxy, carboxyalkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylcarbonyl, aryl, aralkyl,arylsulfonyl, arylcarbonyl, aryloxycarbonyl, aminosulfonyl,aminocarbonyl, heteroaryl, heteroaralkyl, heteroarylsulfonyl,heteroarylcarbonyl, heteroaryloxycarbonyl, heterocyclyl,heterocyclylalkyl heterocyclylsulfonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl monosubstituted amino, or disubstituted aminowherein the aromatic ring in R^(f) is optionally substituted with one,two, or three substituents independently selected from alkyl, alkoxy,halo, haloalkyl, haloalkoxy, hydroxy, carboxy, alkoxycarbonyl,monosubstituted amino, disubstituted amino, or acylamino; or apharmaceutically acceptable salts thereof.
 2. The compound of claim 1wherein: R^(d1) is hydrogen, hydroxy, alkoxy, amino, alkylamino ordialkylamino; R^(d) and R^(d2) are independently hydrogen, alkyl, halo,alkoxy, alkylthio, or alkylsulfonyl; and R^(d3) is a group of formula:

optionally substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl,alkoxy, cycloalkoxy, nitro, amkylcarbonylamino, cycloalkylcarbonylamino,cycloalkylalkylcarbonylamino, alkyloxycarbonylaminol amino, alkylamino,dialkylamino, or —NHCONRR′ where R is hydrogen or alkyl and R′ ishydrogen, alkyl, cycloalkyl, or cycloalkylalkyl wherein cycloalkyl andcycloalkylalkyl are optionally substituted with one, two or three alkyl.3. The compound of claim 1 wherein: R^(d1) is hydrogen, hydroxy, alkoxy,amino, alkylamino or dialkylamino; R^(d) and R^(d2) are independentlyhydrogen, alkyl, halo, alkoxy, alkylthio, or alkylsulfonyl; and R^(d3)is a group of formula:

optionally substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl,alkoxy, cycloalkoxy, nitro, amkylcarbonylamino, cycloalkylcarbonylamino,cycloalkylalkylcarbonylamino, alkyloxycarbonylamino, amino, alkylamino,dialkylamino, or —NHCONRR′ where R is hydrogen or alkyl and R′ ishydrogen, alkyl, cycloalkyl, or cycloalkylalkyl wherein cycloalkyl andcycloalkylalkyl are optionally substituted with one, two or three alkyl.4. The compound of claim 1 wherein: R^(d1) is hydrogen, hydroxy, alkoxy,amino, alkylamino or dialkylamino; R^(d) and R^(d2) are independentlyhydrogen, alkyl, halo, alkoxy, alkylthio, or alkylsulfonyl; and R^(d3)is a group of formula:

optionally substituted with halo, alkyl, cycloalkyl, cycloalkylalkyl,alkoxy, cycloalkoxy, nitro, amkylcarbonylamino, cycloalkylcarbonylamino,cycloalkylalkylcarbonylamino, alkyloxycarbonylamino, amino, alkylamino,dialkylamino, or —NHCONRR′ where R is hydrogen or alkyl and R′ ishydrogen, alkyl, cycloalkyl, or cycloalkylalkyl wherein cycloalkyl andcycloalkylalkyl are optionally substituted with one, two or three alkyl.5. The compound of any of the claims 1, 2, 3, or 4 wherein R^(d3) isoptionally substituted with methyl, ethyl, n-propyl, i-propyl, n-butyl,1-methylpropyl, 2-methylpropyl, tert-butyl, 2,2,-dimethylpropyl,1,2-dimethylpropyl, 1,2,2-trimethylpropyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl and cyclohexylmethyl.
 6. The compound of any of theclaims 1, 2, 3 or 4 wherein R^(d3) is optionally substituted with amino,methylamino, ethylamino, propylamino, 1-methylethylamino,1,1-dimethylethylamino, 2-methylpropylamino, 1-methylpropylamino,2,2-dimethyipropylamino, 1,2-dimethylpropylamino,1,1-dimethylpropylamino, methylcarbonylamino, ethylcarbonylamino,propylcarbonylamino, 1-methylethylcarbonylamino,1,1-dimethylethylcarbonylamino, 2-methyipropylcarbonylamino,1-methylpropylcarbonylamino, 2,2-dimethylpropylcarbonylamino,1,2-dimethylpropylcarbonylamino, 1,1-dimethylpropylcarbonylamino,cyclopropylcarbonylamino, cyclobutylcarbonylamino,cyclopentylcarbonylamino, cyclohexylcarbonylamino,cyclopropylmethylcarbonylamino, cyclobutylmethylcarbonylamino,cyclopentylmethylcarbonylamino, cyclohexylmethylcarbonylamino,methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,1-methylethoxycarbonylamino, 1,1-dimethyl-ethoxycarbonylamino,2-methyipropoxycarbonylamino, 1-methyipropoxycarbonylamino,2,2-dimethyipropoxycarbonylamino, 1,2-dimethylpropoxycarbonylamino, or1,1-dimethyipropoxy-carbonylamino.
 7. A compound of Formula (I):

wherein E is —COCONR⁵R⁶, —COCF₂CONR⁵R⁶, —COCF₂C(O)OR⁵, —COCOR⁷,—COCF₂R^(8,) —COR⁹, or —B(OR¹³)₂ where R⁵, R⁶, R⁷, R⁹, and each R¹³ isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, or heterocyclylalkyl and R⁸ is halo, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, or heterocyclylalkyl wherein the aliphatic,alicyclic and aromatic groups in E are optionally substituted with one,two, or three R^(a) independently selected from hydroxy, alkoxy,aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, amino,monosubstituted amino, disubstituted amino, alkylsulfonyl, arylsulfonyl,carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl,alkenylaminocarbonyl, acylamino, aminocarbonyl, halo, or cyano andfurther wherein the aromatic ring in R^(a) is optionally substitutedwith one, two, or three substituents independently selected from alkyl,alkoxy, halo, haloalkyl, haloalkoxy, carboxy, or carboxyalkyl; R¹ isalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkylwherein the aliphatic, alicyclic and aromatic groups in R¹ areoptionally substituted with one or two R^(b) independently selected fromhydroxy, alkoxy, aryloxy. heteroaryloxy, alkylthio. arylthio,heteroarvlthio, amino, monosubstituted amino, disubstituted amino,alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, acylamino,aminocarbonyl, halo, or cyano and further wherein the aromatic ring inR^(b) is optionally substituted with one, two, or three substituentsindependently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy,carboxy, or carboxyalkyl; X is —O—, —NH—, —S—, —SO—, or —SO₂—; R³ isalkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkylwherein the aliphatic, alicyclic and aromatic groups in R³ areoptionally substituted with one or two R^(c) independently selected fromhydroxy, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio,heteroarylthio, amino, monosubstituted amino, disubstituted amino,alkylsulfonyl, arylsulfonyl, carboxy, alkoxycarbonyl, acylamino,aminocarbonyl, halo, or cyano and further wherein the aromatic ring inR^(c) is optionally substituted with one, two, or three substituentsindependently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy,carboxy, or carboxyalkyl; Y is —OC(O)NH—, —NR¹⁴—C(O)NH—, orNR¹⁴C(O)O—where each R¹⁴ selected from hydrogen, alkyl optionallysubstituted with hydroxy, alkoxy, amino, monosubstituted amino,disubstituted amino, aryl, heteroaryl or heterocyclyl; R² is a group offormula (b):

where: R^(d1) is hydrogen, hydroxy, alkoxy, amino, alkylamino,dialkylamino, haloalkoxy or alkylsulfonyl; R^(d) and R^(d2) areindependently hydrogen, alkyl, halo, alkoxy, alkylthio, oralkylsulfonyl; or R^(d1) and R^(d) or R^(d1) and R^(d2) together withthe carbon atoms to which they are attached form 4, 5, or 6-atomheterocyclyl ring wherein one or two ring atoms are replaced by oxygenor —N— where the heterocyclyl ring is optionally substituted with one ortwo alkyl; R^(d3) is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl;wherein at least one of R^(d), R^(d1), R^(d2) and R ^(d3) is other thanhydrogen; and R ⁴ is alkyl; or a pharmaceutically acceptable saltthereof.
 8. The compound of claim 7 wherein R^(d1) is hydrogen, hydroxy,alkoxy, amino, alkylamino or dialkylamino; R^(d) and R^(d2) areindependently hydrogen, alkyl, halo, alkoxy, alkylthio, oralkylsulfonyl; and R^(d3) is a hydrogen, alkyl or cycloalkyl.
 9. Thecompound of claim 7 wherein R^(d1) is hydrogen, hydroxy, methoxy,ethoxy, n-propoxy, iso-propoxy, methylamino, ethylamino, n-propylamino,isopropylamino, dimethylamino, methylethylamino, methyl(n-propyl)aminoor methyl(isopropyl)amino; and R^(d) and R^(d2) are independently,fluoro, chloro, methyl, methoxy, ethoxy, thiomethyl or methylsulfonyl.10. The compound of claim 7 wherein R^(d1) is hydrogen, hydroxy,methoxy, or ethoxy; and R^(d) and R^(d2) are independently, hydrogen,fluoro, chloro or methyl.
 11. The compound of claim 7 wherein R^(d1) ismethoxy or ethoxy; and R^(d), R^(d2) and R^(d3) are each hydrogen. 12.The compound of any of the claims 1, 2, 3 or 4, wherein X is —O—; R¹ isalkyl or cycloalkylalkyl; and R³ is 1-methylethyl, 1 -methylpropyl,tert-butyl, cyclopropyl, phenyl, or cyclohexyl.
 13. The compound of anyof the claims 1, 2, 3 or 4 wherein X is —O—; R¹ is cyclobutylmethyl,ethyl, or n-propyl; and R³ is tert-butyl or cyclohexyl.
 14. The compoundof any of the claims 1, 2, 3 or 4, wherein E is —COCONHR⁶ where R⁶ ishydrogen, alkyl, cycloalkyl, aralkyl, or heteroaralkyl wherein thearomatic ring is optionally substituted with one or two halo.
 15. Thecompound of any of the claims 1, 2, 3 or 4, wherein E is —COCONHR⁶ whereR⁶ is cyclopropyl.
 16. The compound of any of the claims 1, 2, 3 or 4,wherein Y is —NHC(O)NH— and R⁴ is alkyl.
 17. The compound of any of theclaims 1, 2, 3 or 4, wherein Y is —OC(O)NH— and R⁴ alkyl.
 18. Thecompound of any of the claims 1, 2, 3 4, wherein Y is —C(O)NH— and R⁴ isalkyl.
 19. A compound having the structure:

or a pharmaceutically acceptable salt thereof.
 20. A compound having thestructure:

or a pharmaceutically acceptable salt thereof.
 21. A diastereomericmixture of compounds represented by the structure:

or a pharmaceutically acceptable salt thereof.
 22. A compound selectedfrom the group consisting of:1-[2S-(3-tert-butylureido)-3,3-dimethylbutyryl]-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclopropylaminooxalylbutyl)amide;1-[2S-(3-tert-butylureido)-3,3-dimethylbutyryl]-4R-(7-methoxy-2-pyrazol-1-ylquinolin-4-yloxy)-pyrrolidine-2-carboxylic acid(1S-cyclobutylmethyl-2-cyclopropylcarbamoyl-2-oxoethyl)amide;1-[2S-(3-tert-butylureido)-3,3-dimethylbutyryl]-4R-(5-chloropyridin-2-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclobutylmethyl-2-cyclopropylcarbamoyl-2-oxoethyl)-amide;{1S[2S-(1S-cyclopropylaminooxalylbutylcarbamoyl)-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-1-carbonyl]-2,2-dimethyipropyl }-carbamic acid tert-butyl ester; {1S-[2S-( 1S-cyclopropylaminooxalylbutylcarbamoyl)-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-1-carbonyl]-2,2-dimethylpropyl }-carbamic acid tert-butyl ester;{1S-[4R-(5-chloropyridin-2-yloxy)-2S-(1S-cyclopropylaminooxalylbutyl-carbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl}-carbamicacid tert-butyl ester;{1S-[4R-(5-chloropyridin-2-yloxy)-2S-(1S-cyclobutylmethyl-2-cyclopropylcarbamoyl-2-oxo-ethylcarbamoyl)-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl}-carbamicacid tert-butyl ester; and1-[2-(3-tert-butylureido)-3,3-dimethyl-butyryl]-4-(5-chloro-pyridin-2-yloxy)-pyrrolidine-2-carboxylicacid (1-cyclopropylaminooxalyl-butyl)-amide.
 23. A pharmaceuticalcomposition comprising a compound of any of the claims 1, 2, 3 or 4, andone or more pharmaceutically acceptable excipients.
 24. A method oftreating hepatitis C infections in a patient comprising administering tothe patient a pharmaceutical composition comprising a compound of any ofthe claims 1, 2, 3- or 4, and one or more pharmaceutically acceptableexcipients.
 25. The compound of claim 1 which is1-[2S-(3-tert-butylureido)-3,3-dimethylbutyryl]-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid (1S-cyclopropylaminooxalylbutyl)amide; or a pharmaceuticallyacceptable salt thereof.
 26. The compound which is1-[2S-(3-tert-butylureido)-3,3-dimethylbutyryl]-4R-(7-methoxy-2-pyrazol-1-yl-quinolin-4-yloxy)-pyrrolidine-2S-carboxylicacid (1R-cyclopropylaminooxalylbutyl)amide; or the sulfate ormethylsulfonate salt thereof.
 27. A pharmaceutical compositioncomprising a compound of claim 14 and one or more pharmaceuticallyacceptable excipients.
 28. A pharmaceutical composition comprising acompound of claim 19 and one or more pharmaceutically acceptableexcipients.
 29. A method of treating hepatitis C infections in a patientcomprising administering to the patient a pharmaceutical compositioncomprising a compound of claim 15, and one or more pharmaceuticallyacceptable excipients.
 30. A method of treating hepatitis C infectionsin a patient comprising administering to the patient a pharmaceuticalcomposition comprising a compound of claim 15, and one or morepharmaceutically acceptable excipients.
 31. A compound selected from thegroup consisting of:1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2S-carboxylicacid(1S-cyclopropylaminooxalyl-butyl)-amide;1-[2S-(3tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2S-carboxylicacid(2-cyclopropylcarbamoyl-1S-cyclopropylmethyl -2-oxo-ethyl)-amide;1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-2-carboxylicacid(2-cyclopropylcarbamoyl-1S-cyclopropylmethyl-2S-oxo-ethyl)-amide;1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-ethoxy-isoquinolin-1-yloxy)-pyrrolidine-2S-carboxylicacid(1S-cyclopropylaminooxalyl-butyl)-amide;1-[2S-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4R-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-2S-carboxylicacid(1S-cyclopropylaminooxalyl-pentyl)-amide;(S)-1-[2-(3-tert-Butylureido)-3,3-dimethylbutyryl]-4-trans-(3-cyclopropyl-6-methoxyisoquinolin-1-yloxy)pyrrolidine-2-(S)-carboxylic acid (1-cyclopropylaminooxalyl-butyl)amideHydrochloride; and1-[2-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-4-(3-methyl-6-methoxyisoquinolin-1-yloxy)-pyrrolidine-2-carboxylicacid(1-cyclopropylaminooxalylbutyl)-amide.